New technologies applicable to bladder hyperthermia Brant A. Inman, MD, MS Cary N. Robertson Associate Professor of Urology
Transcript
New technologies applicable to bladder hyperthermia Brant A Inman MD MS Cary N Robertson Associate Professor of Urology
All Rights Reserved Duke Medicine 2011
Learning objectives
bull Understand how fever-range hyperthermia can influence cancer biology
bull Understand fundamental concepts of heat-targeted drug delivery for bladder cancer
bull Describe some novel applications of hyperthermia in bladder cancer
2
Coley Proc Royal Soc Med 1910
Coley Proc Royal Soc Med 1910
Owusu et al Biomed Res Int 2013
All Rights Reserved Duke Medicine 2011
The key advantages of hyperthermia
1 Minimal toxicity
2 Can be administered in many ways
3 Can be combined with other therapies ndash Synergistic (not just additive)
4 Can be combined with immunotherapies
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Learning objectives
bull Understand how fever-range hyperthermia can influence cancer biology
bull Understand fundamental concepts of heat-targeted drug delivery for bladder cancer
bull Describe some novel applications of hyperthermia in bladder cancer
2
Coley Proc Royal Soc Med 1910
Coley Proc Royal Soc Med 1910
Owusu et al Biomed Res Int 2013
All Rights Reserved Duke Medicine 2011
The key advantages of hyperthermia
1 Minimal toxicity
2 Can be administered in many ways
3 Can be combined with other therapies ndash Synergistic (not just additive)
4 Can be combined with immunotherapies
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Coley Proc Royal Soc Med 1910
Coley Proc Royal Soc Med 1910
Owusu et al Biomed Res Int 2013
All Rights Reserved Duke Medicine 2011
The key advantages of hyperthermia
1 Minimal toxicity
2 Can be administered in many ways
3 Can be combined with other therapies ndash Synergistic (not just additive)
4 Can be combined with immunotherapies
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Coley Proc Royal Soc Med 1910
Owusu et al Biomed Res Int 2013
All Rights Reserved Duke Medicine 2011
The key advantages of hyperthermia
1 Minimal toxicity
2 Can be administered in many ways
3 Can be combined with other therapies ndash Synergistic (not just additive)
4 Can be combined with immunotherapies
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Owusu et al Biomed Res Int 2013
All Rights Reserved Duke Medicine 2011
The key advantages of hyperthermia
1 Minimal toxicity
2 Can be administered in many ways
3 Can be combined with other therapies ndash Synergistic (not just additive)
4 Can be combined with immunotherapies
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
The key advantages of hyperthermia
1 Minimal toxicity
2 Can be administered in many ways
3 Can be combined with other therapies ndash Synergistic (not just additive)
4 Can be combined with immunotherapies
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Conceptual model
Hyperthermia
Drug delivery
Drug activity
Immunity
Tumor damage
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Issels Eur J Cancer 2008
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Heating options for the bladder
Page 9
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Deep regional hyperthermia
BSDPyrexar
AMC
Alba 4D
Thermotron
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Deep regional hyperthermia PROS CONS
1 Wider field of heating 1 Large device 2 Treatment planning 2 RF shielded room 3 Used for a variety of tumors
3 High cost
4 Slow heating 5 Not generalizable for NMIBC 6 Contraindicated with devices or hip replacements
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Yuan et al Med Phys 2012
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Yuan et al Med Phys 2012
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Inman et al Int J Hyperthermia 2014
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Salahi et al Int J Hyperthermia 2012
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Salahi et al Int J Hyperthermia 2012
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Synergo SB-TS 101 device
Intravesical radiofrequency antennae
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Intravesical RF antennae
PROS CONS 1 Most well studied 1 Medium size device 2 Generalizable in NMIBC 2 High cost 3 No need for physics team 3 Bladder burns
( significance) 4 Contraindicated with devices
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Intravesical conduction
Elmedical BWT Combat BRS
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Intravesical conductive devices
PROS CONS 1 Small device 1 Limited to bladder 2 Inexpensive 2 Bubble accumulation 3 Generalizable for NMIBC 3 Not for MIBC () 4 Can trigger heat-targetable drugs 5 Can be used with other devices and hip prostheses 6 No need for physics team
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Submillimeter fiber optic microprobes and silicone germanium thermistors
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Bladder
Internal iliac vein
Temperature probe placement for heat mapping
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Sousa et al Int J Hypertherm 2014
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Intravesical magnetic nanoparticle hyperthermia
Page 30
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Oliviera et al Int J Hyperthermia 2013
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Huang et al Int J Nanomed 2012
Iron oxides (eg magnetite)
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Rodrigues et al Int J Hypertherm 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Oliviera et al Proc SPIE 2013
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Oliviera et al Proc SPIE 2013
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Thermally sensitive liposomes for drug delivery
Page 38
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Why use a thermally sensitive drug
bull Can achieve drug concentrations 10-30X higher in the tumor
bull Can target drug delivery to specific anatomical locations (by heating those spots)
bull Can reduce drug dose because of better delivery and decrease systemic toxicity
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Ponce et al Int J Hyperthermia 2006
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Landon et al Open Nanomed J 2011
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Using heat-activated drugs makes sense
bull Improve tissue drug levels (increase efficacy) bull Might allow for lower systemic doses bull Target drug to organssites of need bull Number of agents growing
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
All Rights Reserved Duke Medicine 2011
Enhancing immune effects of hyperthermia
Page 45
MHCAg
B7-12 CD28
TCR
APC T cell
T cell response
Antigen presentation to the T cell
Coinhibition impairs IL-2 response
Costimulation and Coinhibition
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
MHCAg
B7-12 CD28
TCR
APC T cell
T cell response
Antigen presentation to the T cell
Coinhibition impairs IL-2 response
Costimulation and Coinhibition
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Coinhibition impairs IL-2 response
Costimulation and Coinhibition
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Costimulation and Coinhibition
Inman BA Frigola X et al Curr Cancer Drug Targets 2007
Costimulation and Coinhibition
Inman BA et al Curr Cancer Drug Targets 2007
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Inman BA et al Cancer 2007
Bladder cancer BCG failure and B7-H1 (PD-L1)
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Inman BA et al Cancer 2007
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Targeting the ligand
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
CP1185666-3
MHCAg
B7-12 CD28
TCR
APC T cell
PD-1 Anti-PD-1
T cell response
Targeting the receptor
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
0
20
40
60
80
100
-2 0 3 7 11 15 18 21 27 31 35
Time (days)
Su
rviv
al (
)
No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
0
50
100
150
200
250
300
350
400
-2 0 3 7 11 15 18 21
Time (days)
Tum
or s
ize
(mm
2)No-treatmentVAC+ control AbVAC+10B5VAC+Gk15VAC+Gk15+10B5
Blocking PD-L1can cure some cancers
Webster WS et al J Immunol 2007
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Chart4
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Survival ()
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
75
100
75
100
100
75
100
75
25
75
75
100
50
0
50
75
100
50
50
75
100
0
50
75
100
50
75
100
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
0
0
0
0
0
3
3
3
3
3
7
7
7
7
7
11
11
11
11
11
15
15
15
15
15
18
18
18
18
18
21
21
21
21
21
27
27
27
27
27
31
31
31
31
31
35
35
35
35
35
Sheet1
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
D3
1
25
35
42
90
70
99
110
130
176
238
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
D5
1
64
81
110
225
144
121
100
100
72
49
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
4
66
78
84
24
0
0
0
0
0
0
av
25
sd
178138522878
142214626533
148436293855
829352156807
598463309931
531060260234
479748197843
50
05020662923
04293688721
03870816987
04407289846
treatment
anti-CD4 250 ug ip on day 12
00243456894
06205369334
01175248296
00205866974
0006395116
00024307496
00178298098
05799302441
04291160905
0149128168
00597598028
00467906282
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
no-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
vac+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
vac+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
vac+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
vac+Gk15+10B5
50
6725
925
11625
6575
4375
2825
25
of survival
-2
0
3
7
11
15
18
21
27
31
35
No-treatment
100
100
100
100
100
75
75
50
50
0
VAC+ control Ab
100
100
100
100
100
100
25
0
VAC+10B5
100
100
100
100
100
100
75
50
50
50
50
VAC+Gk15
100
100
100
100
75
75
75
75
75
75
75
VAC+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
Sheet1
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
86938675705
81034971874
72341781381
120277457018
178138522878
129099444874
148408220797
133010024685
182938969787
142214626533
178955301682
250532765655
203695033486
47085029468
148436293855
419841239836
312996272608
424735211632
815250472759
829352156807
582065288434
441323766261
667551496141
1029186572007
598463309931
677200118133
325525216637
670447611674
1389181413639
531060260234
792969104064
278373250631
1114312194435
1434000813575
479748197843
Sheet2
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
Sheet3
no-treatment
vac+ control Ab
vac+10B5
Days after treatment
Rumor sizes (mm2)
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
Chart1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Time (days)
Tumor size (mm2)
2925
265
335
48
453333333333
35
3775
4275
51
626666666667
5775
675
5175
1055
866666666667
92
1095
89
1325
80
142
1645
10375
10825
396666666667
178
2055
1145
10675
18
218
27075
16875
9875
43333333333
256
313
1885
104
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
-2
-2
-2
-2
-2
86938675705
86938675705
72341781381
120277457018
185831464864
0
0
0
0
0
129099444874
129099444874
133010024685
182938969787
13316656237
3
3
3
3
3
178955301682
178955301682
203695033486
47085029468
112398102001
7
7
7
7
7
419841239836
419841239836
424735211632
815250472759
493254498206
11
11
11
11
11
582065288434
582065288434
667551496141
1029186572007
359212100761
15
15
15
15
15
677200118133
677200118133
670447611674
1389181413639
158745078664
18
18
18
18
18
792969104064
792969104064
1114312194435
1434000813575
45092497528
21
21
21
21
21
547806230949
1211018854794
1847809513992
0
Sheet1
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
RENCA
9x10-5 cells sc on 6242005
7905gk15
71405gk1510b5
7605
7805
71105
71505
71905
72305
72605
72905
8405
8805
81205
day
12
14
17
21
25
29
32
35
41
45
day after tx
-2
0
3
7
11
15
18
21
27
31
D1
1
20
20
48
80
117
135
228
266
380
x
2
25
30
45
50
91
187
180
180
242
299
3
32
40
54
88
135
120
140
150
234
x
4
40
50
84
150
225
270
324
247
462
x
av
21075
sd
86938675705
129099444874
178955301682
419841239836
582065288434
677200118133
792969104064
547806230949
1108798148147
sem
D2
1
35
56
88
130
180
224
255
320
420
x
vac
2
25
40
90
140
220
240
240
312
330
x
3
30
35
50
96
128
190
299
299
nec
x
4
16
20
42
72
130
168
289
324
420
x
av
31375
sd
81034971874
148408220797
250532765655
312996272608
441323766261
325525216637
278373250631
110264832713
519615242271
D3
1
25
35
42
90
70
99
110
130
176
238
necrosis
vac+10b5
2
30
30
30
36
30
36
49
49
64
100
169
240
3
40
60
77
140
180
198
300
315
300
x
4
39
46
58
90
135
125
216
260
330
x
av
1885
sd
72341781381
133010024685
203695033486
424735211632
667551496141
670447611674
1114312194435
1211018854794
1221297124645
04666248089
01797421573
00503359853
01260480308
00850582355
D4
1
48
56
96
96
45
25
0
0
0
0
0
gk15
2
35
28
54
70
24
0
0
0
0
0
0
vac
3
64
72
168
252
252
306
304
380
441
x
4
45
48
104
112
112
96
91
36
20
16
9
0
av
104
sd
120277457018
182938969787
47085029468
815250472759
1029186572007
1389181413639
1434000813575
1847809513992
2173712262467
D5
gk15+10b5
2
40
54
77
99
49
30
9
0
0
0
0
0
vac
3
30
56
99
117
70
24
4
0
0
0
0
0
4
66
78
84
24
0
0
0
0
0
0
0
0
av
0
sd
185831464864
13316656237
112398102001
493254498206
359212100761
158745078664
45092497528
0
0
03281414271
03314045828
03165080251
03851130654
treatment
anti-CD4 250 ug ip on day 12
00593546365
07415532379
00452156842
00111546187
00061144115
00012840537
00458806892
08052998984
01975242335
00624885966
00549798149
00464753309
6-Jul
gk15
8-Jul
vac10b5
-2
0
3
7
11
15
18
21
11-Jul
vac10b5
No-treatment
2925
35
5775
92
142
178
218
256
14-Jul
10b5gk15
VAC+ control Ab
265
3775
675
1095
1645
2055
27075
313
18-Jul
vac10b5
VAC+10B5
335
4275
5175
89
10375
1145
16875
1885
21-Jul
10b5gk15
VAC+Gk15
48
51
1055
1325
10825
10675
9875
104
23-Jul
avc
VAC+Gk15+10B5
453333333333
626666666667
866666666667
80
396666666667
18
43333333333
0
of survival
-2
0
3
7
11
15
18
21
27
31
35
no-treatment
100
100
100
100
100
75
75
50
50
0
vac+ control Ab
100
100
100
100
100
100
25
0
vac+10B5
100
100
100
100
100
100
75
50
50
50
50
vac+Gk15
100
100
100
100
75
75
75
75
75
75
75
vac+Gk15+10B5
100
100
100
100
100
100
100
100
100
100
100
Sheet1
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
86938675705
86938675705
72341781381
120277457018
185831464864
129099444874
129099444874
133010024685
182938969787
13316656237
178955301682
178955301682
203695033486
47085029468
112398102001
419841239836
419841239836
424735211632
815250472759
493254498206
582065288434
582065288434
667551496141
1029186572007
359212100761
677200118133
677200118133
670447611674
1389181413639
158745078664
792969104064
792969104064
1114312194435
1434000813575
45092497528
547806230949
1211018854794
1847809513992
0
Sheet2
No-treatment
VAC+ control Ab
VAC+10B5
VAC+Gk15
VAC+Gk15+10B5
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Sheet3
No-treatment
VAC+ control Ab
VAC+10B5
Days after treatment
Rumor sizes (mm2)
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
no-treatment
vac+ control Ab
vac+10B5
vac+Gk15
vac+Gk15+10B5
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Powles et al Nature 2014
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
All Rights Reserved Duke Medicine 2011
Combining HT with immunotherapy makes sense
bull HT itself is immunogenic (auto-vaccination) ndash Heat shock proteins ndash Upregulate MHC I
bull HT encourages leukocyte trafficking
ndash Selectin and integrin regulation ndash Endothelial changes
bull HT activates immune cells
ndash DCs and NKs
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
All Rights Reserved Duke Medicine 2011
Synergistic immuno photo nanotherapy (Symphony)
Page 56
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
TEM
Si
mul
atio
n
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Marker
Visible Tumor
Thermal Camera 1x [20 μm Resolution]
Thermal Camera 4x [5 μm Resolution]
8 mm dia Window Chamber and Clip
Permanent Marker
Warmer Nanostar Clusters FLIR
A6703sc bull Best IR camera available (5 μm resolution) bull Can be used with Saphire or BaF2 windows bull Markersscratches can be used as references bull Sees nanostars heating (2 min laser exposure) bull Could map fever range immune response
Visible Tumor
High Resolution Thermal Imaging
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Visible Tumor
Bright field Imaging [1 μm Resolution]
bull Scanning stage microscopy with Zeiss AxioSkop II (fluorescence or bright field)
bull Can be used with Saphire or BaF2 windows bull Diamond scratches can be used as references bull Sees CD4 accrual (30 min after heating) bull Could map fever range immune response
Visible Tumor
Immune System (CD4) Fluorescence
Scratch
Fluorescent CD4 Cluster
Fluorescence Imaging [5 μm Resolution]
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Before treatment 6 days after heating GFP myeloid
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
Treated side Untreated side
Nanostar HT
Nanostar HT +
Immunotherapy
Immunotherapy
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
All Rights Reserved Duke Medicine 2011
Summary 1 What does the future hold
bull Different devices for different applications ndash Office devices for NMIBC ndash Hospital (possibly office) devices for MIBC
bull New heat-targeted drugs ndash Deliver drug better (more drug to tumor) ndash Activate drug (same drug works better) ndash Less toxic (lower doses)
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
Team Science
Slide Number 1
Learning objectives
Slide Number 3
Slide Number 4
Slide Number 5
The key advantages of hyperthermia
Slide Number 7
Slide Number 8
Slide Number 9
Slide Number 10
Deep regional hyperthermia
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Slide Number 19
Slide Number 20
Intravesical RF antennae
Slide Number 22
Intravesical conductive devices
Slide Number 24
Slide Number 25
Slide Number 26
Slide Number 27
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Slide Number 32
Slide Number 33
Slide Number 34
Slide Number 35
Slide Number 36
Slide Number 37
Slide Number 38
Why use a thermally sensitive drug
Slide Number 40
Slide Number 41
Slide Number 42
Slide Number 43
Using heat-activated drugs makes sense
Slide Number 45
Slide Number 46
Slide Number 47
Costimulation and Coinhibition
Slide Number 49
Slide Number 50
Slide Number 51
Targeting the receptor
Blocking PD-L1can cure some cancers
Slide Number 54
Combining HT with immunotherapy makes sense
Slide Number 56
Slide Number 57
Slide Number 58
Slide Number 59
High Resolution Thermal Imaging
Immune System (CD4) Fluorescence
Slide Number 62
Slide Number 63
Summary 1 What does the future hold
Summary 2 What does the future hold
Slide Number 66
Slide Number 67
All Rights Reserved Duke Medicine 2011
Summary 2 What does the future hold
bull Combinations with immunotherapy ndash Use HT as a auto-vaccination method ndash Use checkpoint inhibitors
bull Nanoparticles may be useful new agents
ndash Could be used intravesically or systemically
![Malignant hyperthermia [final]](https://static.documents.pub/doc/80x56/58ceb1b71a28abb2218b5123/malignant-hyperthermia-final.jpg)
