Optimization of fractionation with immunotherapy
Silvia Formenti, M.D.
Weill Cornell Medical College
New York Presbyterian Hospital
New York, NY
This presentation is the intellectual property of the presenter. Contact [email protected] for permission to reprint/distribute
Grant/Research support from: Bristol Myers Squibb, Varian, Eli-Lilly,
Janssen, Regeneron, Eisai, Merck
Honoraria from: Bayer, Bristol Myers Squibb, Varian, ViewRay, Elekta,
Janssen, Regeneron, GlaxoSmithKline, Eisai, Astra Zeneca, MedImmune,
Merck US, EMD Serono, Sanofi
I will discuss the following off label use and/or investigational use in my presentation:
Ipilimumab (BMS)
Disclosures
Cancer: A Tumor/Host Interaction
Normal cell
Tumor cells
Immune cell
Elimination
Protection
Immune
rejection
Equilibrium Escape
a
Cancer
ProgressionResult of escape:less immunogenic tumor in a more
tumor-immune-tolerant host
How do standard anti-cancer treatments interfere with
this landscape ?
This presentation is the intellectual property of the presenter. Contact [email protected] for permission to reprint/distribute.
Radiotherapy to convert the tumor into an in situ vaccine
IJROBP, 2004, 2005 IJROBP, 2012
Out of field,distant sites
ABSCOPAL EFFECTS ARE RARE
IMMUNOSUPPRESSION DOMINATES IN
ESTABLISHED TUMORS
Vesely MD, 2011, Annu.Rev.Immunol 29:235-71
Clinical Cancer Res 2005
1 2 3 4 5 6 7 8 90
50
100
150
250
500
750
1000
IFNδ
(pg/m
L)
Strain
RT
α-CD1d
BALB/c WT NKT-/-
-
--
+
- - - - +
+
+
- +
++ -
-
-
-
+
- - -
- +
++
α-CTLA4
AH-1-A5
pMCMV
***
***
**
*
**g
AH1
Tumor irradiation + CTLA-4 blockade
Primary tumor
Lung metastases
Anti-CTLA-4
mAb 9H10
4T1 mouse model of metastatic breast cancer
Experimental Endpoints: - Primary Tumor growth
- Lung metastasis - Immune response evaluation
Jim Allison
• Synergy of focal radiotherapy and immune checkpoint blockade
• Mechanisms of radiation-induced immunogenicity
- adjuvanticity
- antigenicity
• Dose/fractionation dependence
Fuertes et al., J Exp Med 2011
Diamond et al., J Exp Med 2011
Radiation-induces IFN-I
CTLs
3
1
2
BATF3-DCs (DC1)
4
5
6
TDLN
IFN-I
n-fo
ld c
ompa
red
to 0
Gy
c
0Gy
3x8G
y20G
y
0Gy
3x8G
y20G
y
Tnfsf10
Hsh2dIfih1Ccl7
Ccl2Gbp3Il18bpZbp1Bst2C2Ifi204Zbp1H28
Zbp1
CfbOas3Irf7Trim30aOas1aOas1a
Dhx58Ccl5Ifih1
Mx2
Mx1Ddx58Ddx58Il1rl1
Rsad2Ifit1
Ifnb1S100a9
4.0
1.0
0.25
Claire Vanpouille-Box
Single dose 30 GY with anti CTLA-4 precludes the abscopal effect
0Gy 0Gy
+
a-CTLA-4
30Gy 3x8Gy 30Gy
+
a-CTLA-4
3x8Gy
+
a-CTLA-4
Irra
dia
ted
sit
eA
bs
co
pa
l s
ite
0200
600
1000
1400
0200
600
1000
1400
14 22 30
14 22 30
Tu
mo
r volu
me (m
m3)
Tu
mo
r volu
me (m
m3)
14 22 30 14 22 30 14 22 30 14 22 30 14 22 30
6/70/7
14 22 30
0/7 0/7
14 22 30 14 22 30 14 22 30 14 22 30
p* p*
p# #
p**p*
p*
RT
a-CTLA-4
12 13 14
14 17 20
Vanpouille-Box et al., Nature Communications, 2017
Claire Vanpouille-Box
Cytoplasmic dsDNA accumulation
depends on RT dose per fractionTSA
shNS
DAPI
dsDNA
RFP
Merge
0Gy 8Gy 20Gy
c
Nature Communications, 2017Cai X, ET AL Molecular Cell. 2014;
Teunis B H GeijtenbeekNature Immunology 11, 979–980 (2010)
Host DNase TREX1 hides HIV from DNA sensors
Single high-dose RT induces TREX1 up-regulation
Nature Communications, 2017
The window of radiation immunogenicity
is determined by dsDNA vs TREX1
MDA-MB-231
4175-TR
Human TNBC
Is dose/fraction clinically relevant?
38
40
36
10
33
16
27
32
43
22 5 9
30
17 1
23
37
44 3 4-100
-50
0
50
100
150
200
250
Mean
tu
mo
r vo
lum
e c
han
ge (
%)
CR
PR
SD
PD
RECIST
38
40
36
10
33
16
27
32
43
22 5 9
30
17 1
23
37
44 3 4-100
-50
0
50
100
150
200
250
Best
tum
or
vo
lum
e c
han
ge (
%)
b c
0 10 20 30 40 500
50
100
Months
Overa
ll s
urv
ival (%
)
d
Median: 7.36 mo95% CI: 4.4-12.62
0 5 10 15 200
50
100
Months
Pro
gre
ssio
n f
ree s
urv
ival (%
)e
0 10 20 30 40 500
50
100
Months
Overa
ll s
urv
ival (%
) PD
CR/PR/SD
p<0.001
f
Median: 3.81 mo95% CI: 3.06-5.49
a
6 Gy 9.5 Gy
Blood sampling PET/CT imaging
Radiation therapy
Days 1 2 3 4 5 22 43 64 88 FUBaseline
Ipilimumab
Blood sampling
PET/CT imaging
g
0 5 10 15 200
50
100
Months
Pro
gre
ssio
n f
ree s
urv
ival (%
)
PD
CR/PR/SD
p<0.001
Abscopal response to RT+Ipilimumab
38
40
36
10
33
16
27
32
43
22 5 9
30
17 1
23
37
44 3 4-100
-50
0
50
100
150
200
250
Mean
tu
mo
r vo
lum
e c
han
ge (
%)
CR
PR
SD
PD
RECIST
38
40
36
10
33
16
27
32
43
22 5 9
30
17 1
23
37
44 3 4-100
-50
0
50
100
150
200
250
Best
tum
or
vo
lum
e c
han
ge (
%)
b c
0 10 20 30 40 500
50
100
Months
Overa
ll s
urv
ival (%
)
d
Median: 7.36 mo95% CI: 4.4-12.62
0 5 10 15 200
50
100
Months
Pro
gre
ssio
n f
ree s
urv
ival (%
)
e
0 10 20 30 40 500
50
100
Months
Overa
ll s
urv
ival (%
) PD
CR/PR/SD
p<0.001
f
Median: 3.81 mo95% CI: 3.06-5.49
a
6 Gy 9.5 Gy
Blood sampling PET/CT imaging
Radiation therapy
Days 1 2 3 4 5 22 43 64 88 FUBaseline
Ipilimumab
Blood sampling
PET/CT imaging
g
0 5 10 15 200
50
100
Months
Pro
gre
ssio
n f
ree s
urv
ival (%
)
PD
CR/PR/SD
p<0.001
Response : 18% (RECIST v1.1)
CR = 2PR = 5SD = 5
PD = 28
Total pts = 39
Radiation “repositioned” Ipilimumab in metastatic
NSCLC: 18% ORR
Nature Medicine, Nov 2018
*
CR/P
R (n
=7)
SD (n
=5)
PD (n
=8)
NE (n
=15)
0
2
4
6
20
30
IFN
b (
pg
/ml)
*
**
***
*
*
Day 22Baseline
CD8 T cells present in the post-treatment blood of pt #4
recognize an immunogenic mutation in KPNA2
(karyopherin A2)
Nature Medicine 2018
p15 not detected in pre-tx tumorp16 detected in pre-tx tumor
HLA-A*24:02
HLA-C*12:03 Tumor cell Mutated peptide
Mutated protein
MHC-I
Mutated peptide (neoantigen) presented on MHC-I complex
Mutated DNA
Mutated KPNA2 in patient 4
Example of a radiation-induced neo-antigen: an epitope from a mutated gene known to be up-regulated by radiation in human cancer cells in vitro and in vivo
=Radiation converts the tumor into an in situ vaccine
Lhuillier et al., Genome Medicine, 2019
Production of
endogenous
adjuvants
Viral mimicry and in situ vaccination by focal RT
Exposure of
neoantigensNature Medicine 2018
45 Gy in 3 fractions for peripheral lung, liver, and abdominal/pelvic; 50 Gy in 5 fractions for central lung and mediastinal/cervical;30 Gy in 3 fractions for osseous and spinal/ paraspinal”
13% ORR
~ Pembrolizumab alone
● Phase II study ● 92 pts w/ metastatic NSCLC
● Pembro +/- RT (8Gy x 3)
● 12-week ORR: 18% vs 36%
● Median PFS: 1.9 vs 6.6 mo
● Median OS: 7.6 vs 15.9 mo
Doubling of ORR (36 VS 18)and median OS (16 m VS 8m )
by adding RT, 8 GyX3, to pembro
Most effect in PDL1 negative
Significantly better intracranial PFS for patients receiving multi-fraction SRS (9 Gy X3)
compared to single-fraction SRS(70% versus 46% at 6 months, p = 0.01)
• Radiation induces viral mimicry with cytosolic DNA accumulation leading to
cGAS/STING pathway activation and IFNb production, with a dose/fraction effect
• Radiation increases tumor immunogenicity by enhancing the expression of
immunogenic mutations
• There is a dose/fraction dependency for the combination of RT with ICB to covert
the tumor into an in situ vaccine
Conclusions
Silvia C. FormentiEncouse Golden Josephine Kang
Andrew BrandmeierJohn Ng
Himanshu NagarEric Ko
J. Keith Dewyngaert
Sandra DemariaClaire Vanpouille-Box
Julie DiamondErik Wennerberg
Claire LhuillierNils RudqvistSheila Spada
Maud CharpentierSamantha Van Nest
Yasmeen SarfrazMaria Rodriguez-Ruiz
Lorenzo GalluzziTakahiro Yamazaki
Aitziber BuqueAi Sato
Marissa Friedman Jonathan J.
Preclinical CoreKarsten PilonesCamille DaviaudJeffrey Kraynak
Clinical CoreMaria Fenton
Sharanya ChandrasekharPragya Yadav
NYUAbraham Chachoua
Benjamin CooperKent FriedmanAdriana Heguy
Robert SchneiderBeatrix M. Ueberheide
Jessica R. Chapman
WCM Biostatistics & EpidemiologyXi Kathy Zhou
FUNDINGNational Cancer Institute R01 CA201246 & R01 R01CA198533The Chemotherapy Foundation BCRFNYU Vittorio Defendi Fellowship in Pathobiology
NIH, NCI Radiation Branch Molykutty J. Aryankalayil
Norman Coleman
Mount SinaiSacha GnjaticNaoko Imai