Mogamulizumab
Targeting CCR4 to Treat CTCL
Madeleine Duvic, MD
Blanche Bender Professor of Cancer Research
Deputy Chairman – Dept of Dermatology
University of Texas MD Anderson Cancer Center
Case 1
• 2000 a healthy 60 year old WM developed pruritus and erythema on back & keratoderma
• 2006 diagnosis “Pityriaisis rubra pilaris”
• Narrow band UVB without improvement.
• 2007 - Sezary 80% erythroderma, pruritus, Increased CD4+CD26- by flow cytometry.
Erythroderma MRSA+ colonizationPruritus, adenopathy, B2 (SS 9,000)
August 2012
Leukemic CTCL vs Sézary Syndrome
• Perivascular infiltrates without supporting epidermotrophism
• CD4+CD26- or CD4+CD7-
• Central memory T-cells
• By flow in blood
• CD4+ T cell infiltrate
CD 25 CD 30
Frontline Therapy
• 2007 – 2012 the patient received combined immunomodulatory therapy
• Extracorporeal photopheresis (ECP) q 4 weeks
• Interferon alpha 3 mil units x 3 x week
with stable disease thru 2009.
• Acitretin added 2010 with stable disease
• 2010 - Gemcitabine x 6 months stopped for hemolytic uremic syndrome ( HUS ) 0.6%
Progression of SS
• Nov 2011-May 2012 restarted immunotherapy
• ECP/bexarotene/interferon
• 700- 900 SS cells (B1), pruritus, erythroderma
• May–August 2012 off therapy MF flared.
• Increased CD4+26- SS cells (4,000 to 9,000 /ul) adenopathy, severe erythroderma with MRSA,
acral keratoderma, and fissures.
What second line therapy would youuse for patient with Sézary Syndrome?
• Histone deacetylase inhibitors- romidepsin or vorinostat?
• Targeted antibody therapy
– Bretuximab vedotin- conjugate Mab to CD30 + MMAE
– Zanolimumab - Mab to CD4+ T-cells
– Alemtuzumab – Mab to CD52 on mature lymphocytes
– Mogamulizumab - Mab to CCR4 (chemokine)
• TBSEB and non-ablative allogeneic SCT
Mogamulizumab• CCR4 - chemokine receptor expressed on helper T cells
and on T-regulatory cells.• CCR4 binding to ligands TARC or MDC on endothelial
cells promotes trafficking of T cells to skin. • First glyco-engineered humanized mAb• Approved for HTLV-1+ adult T cell lymphoma.• Defucosylation of the antibody Fc backbone increases
ADCC compared to other mAbs.• Phase I/II clinical dose finding study • Phase 3 randomized trial vs vorinostat for improved
PFS
Remer et al. Immunotherapy 2014, 6(11): 1187-206
Asn297
: N-acetylglucosamine
: bisec GlcNAc
: Mannose
: Galactose
: Sialic acid
: Fucose
KW-0761: Humanized Defucosylated Monoclonal
Antibody “Mogamulizumab”Enhanced ADCC
(Potelligent®)
• Antibody backbone lacks fucose
• Leads to an increase in ADCC
activity compared to conventional
antibodies
Fucose
Ishida et al, Clin Cancer Res 2003;9:3625
Expression of CCR4 Receptoron skin homing CD4+ lymphocytes
ALK-negative
ALCL
MF
(transformed)
PTCL-U
Ishida T, et al. Clin Cancer Res. 2004 Aug 15;10(16):5494-500.
CC chemokine receptor 4 (CCR4) in CTCL
Immunohistochemistry staining: CCR4+ atypical T cells in Pautrier'smicroabscess of MF skin lesions
( Ni and Duvic, unpublished data)
Flow cytometry: CD4+CCR4+ T cells in Sézary syndrome patient’s blood
HE
CCR4
Fierro et al, Dermatology, 2006, 213: 284-292
CCR4 Treatment Schedule Phase I/II0.1,0.5,1 mg/kg q week x 4 then every 2 weeks
•Patients with CR are given up to 2 additional courses
•Patients with PR/SD given infusion every other week
until disease progression or withdrawal
•No DLT – 1 mg/kg chosen for Phase II
Course 1 Course 2 Course 32 wk
observation
Results of Phase I/II Multi-center trialCCR4 Global Composite Response
Patient Subgroups ORR
Number of patients
CR PR SD PD
Mycosis Fungoides
(N=21)29% 1 5 11 4
Sezary Syndrome
(N=17)47% 1 7 7 2
TOTAL
(N=38)37% 2 12 18 6
• Overall ORR of 37% vs 47% in Sezary patients
• Multi-center Phase III CCR4 vs vorinostat trial
Duvic et al. Blood Jan 20 epub 2015
Pan histone deacetylase inhibitor
Romidepsin
ORR 34% (6 CRs) in 95 treated patients
• Time to response 2 mos, duration 15 months
• 40% (38 pts) >50% decrease in mSWAT or EE
• 43% had improved pruritus
• 39% OR in 37pts with B1 or B2 involvement
• 31% (4 of 13) w B2 responded
Whittaker et al JCO October 2010 vol 28, 4485
erythroderma
pruritus
Skin mswat
nodes
Phase III Multicenter TrialCCR4 antibody (Mogamulizumab) vs vorinostat
March 2013 CCR4-mAb
July 2013 cycle 5
SS cells gone, nodes smaller
Mswat = partial response
October 2013 CR skin,
blood, pruritus resolved
Photodermatitis:
Fishing on Bactrim and
Drug rash course 14 -23
Complete response: 3/2014
3/2015 - ongoing off drug
66 y/o male treated > one year: PR blood C1D29 and CR at C3D1, PR in skin at C8D1, CR at C9D1. New hypersensitivy pruritic rash with eos at C14- C23
BL C8D1-PR C18 D1-CR C24 D28 CR
Baseline C8D1- PR C18 D1- CR C24 D28- CR
0
20
40
60
80
100
120
140
mSwat
CD4+ CD26-
Duvic et al. JCO 28: No 14 MAY 10, 2010
CCR4 Antibody normalizes Sézary cells in blood
%CD4+CD26-
AbsoluteCD3+CD26-
0 102
103
104
105
CD26
0
102
103
104
105
CD
3
0 102
103
104
105
CD26
0
102
103
104
105
CD
3 CD3+CD4neg
Normal CD3+CD4+
Lymphoma cells
Baseline Cycle 5 D1- PR Cycle 10 D1-CR
Baseline
Cycle 10 D1- CR nodes
CCR4 in Female patient cleared skin, nodes, blood and BM
Partial Response Case 2SS cells at C3D1 - Skin at C6D1
0
20
40
60
80
100
120
140
Baseline C2D1 C3D1 C4D1 C5D1 C6D1 C7D1 C8D1
mSwat
CD4+ CD26-
Skin response by mswat
Partial response
Sézary
cells CR
Best Response by Compartment:Patients with >B1 Blood Involvement
• 7/15 (47%) of patients responded to treatment
• 13/15 (87%) had response in blood
• 7/15 (47%) had CR in blood
Severity of Most Frequent AEs
0 5 10 15
Nausea
Chills
Headache
Pyrexia
Drug eruption
Diarrhea
Vomiting
Fatigue
Pruritis
Dizziness
Upper RTI
Arthralgia
No. of patients
Mild
Moderate
Severe
Duvic et al. Blood Jan 20 epub 2015
Drug Eruption
Pt. 02-MDACC Pt. 05-MDACC
Six patients had drug eruptions not consistent with underlying disease
– Four patients discontinued treatment due to rash
– Use of systemic steroids for treatment of rash not permitted by protocol
Rash at different cycles during CCR4
C14 D28 C20D28 C23D28
Skin with mild superficial perivascular lymphocytic infiltrate; perivascular dermatitis
Superficial perivascular dermatitis, consistent with a dermal hypersensitivity reaction.
Spongiotic and psoriasiform dermatitis
Translational StudyMaterials & Methods
• Peripheral blood mononuclear cells (PBMCs) were collected from 20 patients (10 with MF and 10 with SS) pre- and 4-6 weeks post-KW-0761 at two centers.
• Flow cytometry analysis: T-regs: CD3+CD4+CD25+CD127-
CCR4+ T-regs: CD3+CD4+CD25+CD127-CCR4+
NK cells: CD3-CD56+CD16+
• Real-time PCR: The relative fold changes of foxp3 and CCR4 mRNA in PBMCs before and after treatment
• The standard 4-hour 51Cr release assay: the cytotoxicity of NK cells in PBMCs before and after treatment
KW-0761 (1mg/Kg)
Sample collecting
Therapy start 1 month
Flow cytometry analysis of tumor cells, T-regs, and NK cells in PBMCs of one CTCL patient pre- and post-treatment x 1 course
A representative of flow plots from Pt #8, MF, stable disease, after one course treatment
LJ PRETREATMENT_03 CCR4-26-3---4----16+56-45.fcs
LYMPHS
CD16+CD56 V450-A
CD
3 P
erC
P-C
y5-5
-A
-10210
010
210
310
410
5
-102
101
103
104
105
32.87%21.33%
3.55%42.26%
LJ POSTTREATMENT_03 CCR4-26-3---4----16+56-45.fcs
LYMPHS
CD16+CD56 V450-A
CD
3 P
erC
P-C
y5-5
-A
-10210
010
210
310
410
5
-102
101
103
104
105
35.55%34.15%
2.07%28.24%
LJ PRETREATMENT_05 7-CCR4 1G1-4-26---3-45.fcs
CD3+CD4+
CD26 APC-A
CD
4 P
erC
P-C
y5-5
-A
-10210
010
210
310
410
5
-102
102
103
104
105
0.00%0.19%
31.39%
68.42%
CD4+CD26-
LJ POSTTREATMENT_05 7-CCR4 1G1-4-26---3-45.fcs
CD3+CD4+
CD26 APC-A
CD
4 P
erC
P-C
y5-5
-A
-10210
010
210
310
410
5
-102
102
103
104
105
0.00%0.00%
46.49%
53.51%
CD4+CD26-
Pre
-Tre
atm
en
tP
ost
-Tre
atm
ent
LJ PRETREATMENT_05 7-CCR4 1G1-4-26---3-45.fcs
CD4+CD26-
CCR41G1 PE-A
CD
4 P
erC
P-C
y5-5
-A
-10210
010
210
310
410
5
-102
102
103
104
105
37.58% 62.42%
0.00% 0.00%
LJ POSTTREATMENT_05 7-CCR4 1G1-4-26---3-45.fcs
CD4+CD26-
CCR41G1 PE-A
CD
4 P
erC
P-C
y5-5
-A
-10210
010
210
310
410
5
-102
102
103
104
105
98.01% 1.99%
0.00% 0.00%
0103 LJ PRETREATMENT_02 25-CCR4 1G1-4-127-3.fcs
T REGS
CCR4 1G1 PE-A
CD
3 V
450-A
-10210
010
210
310
410
5
-102
100
103
104
105
4.07% 95.93%
0.00% 0.00%
LJ 013 C2 DAY1 INDIRECT_02 25-CCR41G1-4-127-3.fcs
T REGS
CCR41G1 PE-A
CD
3 V
450-A
-10210
010
210
310
410
5
-102
100
103
104
105
90.00% 10.00%
0.00% 0.00%
0103 LJ PRETREATMENT_02 25-CCR4 1G1-4-127-3.fcs
CD3+CD4+
CD127 APC-A
CD
25 F
ITC
-A
-10210
010
210
310
410
5
-102
100
103
104
105
0.56%1.17%
82.73%15.54%
LJ 013 C2 DAY1 INDIRECT_02 25-CCR41G1-4-127-3.fcs
CD3+CD4+
CD127 APC-A
CD
25 F
ITC
-A
-10210
010
210
310
410
5
-102
100
103
104
105
0.58%0.48%
63.91%35.03%
A. CD3+CD4+CD26-tumor cells
B. CCR4+ tumor cells
C. CD3+CD4+CD25+ CD127- T-regs
E. CD3-CD16+ CD56+ NK cells
D. CCR4+ T-regs
Anti-CCR4 decreased CD3+CD4+CD25+CD127- T-regs
15/20 (75%) patients had detectable T-regs at baseline
15/15 (100%) patients had decreased T-regs in percentages (Figure B) and absolute #(Figure C) after treatment
* Patients who had no detectable T-regs (Figure A)
Pre Post
Pre Post
0,0
1,0
2,0
3,0
4,0
1 4 5 6 7 8 9 16 17 19 10 11 2 3 12 13 14 15 18 20
MF SS
T-re
gs o
f ly
mp
ho
cyte
s (
%)
A.A.
**** *
C.P < 0.05
34.50
5.65
-20.0
0.0
20.0
40.0
60.0
80.0
100.0T
-re
gs o
f ly
mp
ho
cyte
s (
/u
l)
1.26
0.390.390.390.39
Pre Post
P<0.01
Pre Post
P<0.01
34.50
5.65
-20.0
0.0
20.0
40.0
60.0
80.0
100.0T
-re
gs o
f ly
mp
ho
cyte
s (
/u
l)
Pre Post
P<0.01
Ni et al. Clin Cancer Res. 2015 Jan 15;21(2):274-85.
**
*
0.00
0.40
0.80
1.20
1.60
Before After Before After
T-regs (%) Foxp3 (fold change)
16.02
22.64
4.92
8.70
0.00
10.00
20.00
30.00
40.00
Before After Before After
NK cells (%) % killing (E:T 50:1)
Effects of anti-CCR4 antibody (KW-0761) on regulatory T cells and natural killer cells in CTCL patients
Ni et al. Clin Cancer Res. 2015 Jan 15;21(2):274-85
% T-regs Foxp3 %NK % Killing
Conclusions
• Mogamulizimab - humanized defucosylatedmAb to skin homing chemokine receptor CCR4
• OR is 47% in SS, 29% in MF, and 37% MF/SS
• Flow cytometry to diagnose SS and monitor response of blood to CCR4 therapy.
• Mogamulizimab depletes malignant T memory SS cells and T-regulatory cells rapidly
• Ongoing Phase III Randomized International Trial of Mogamulizimab vs vorinostat PFS
Acknowledgements
MD Anderson Cancer Center
Dept. of Dermatology
Xia Ni, MD, PhD
Rakhshandra Talpur, MD
Meghali Goswami, BS
Seema Daulat, MD
Carol Wilson, BS, RN
Residents, Fellows
Dept. of Hematopathology
Jeffrey Jorgensen, MD, PhD
Pramoda Challagundla, MS
Dept. of Stem Cell Transplantation William Decker, PhD
Stanford Cancer Center
Dept. of DermatologyYoun Kim, MDMichelle CallejasFarah Abdulla, MD
Kyowa Hakko Kirin, Co., Ltd.Nehal Mohamed, PhDKaren Dwyer
Takeshi Takahashi, PhD
Research fundingInvestigator initiated study –Kyowa Hakko Kirin, Co., Ltd.
Sherry Anderson Foundation
Alemtuzumab Anti-CD52 mAb
Outcome, % Phase II Study: Sweden[1]
Advanced MF/SS(n = 22)
Phase II Study: Northwestern[2]
E-CTCL(N = 19)
Open label: Chicago[3]
Heavily pre-tx E-CTCL(n = 19)
ORR 55 79 84
CR 32 47 47
PR 23 32 37
TTF, mo(range)
12 (5 - 32+) NR NR
DOR, mo(range)
NR 7 (1 – 39)NR
PFS, mo NR NR 6
OS, mo NR NR 41
1. Lundin J, et al. Blood. 2003;101:4267-4272. 2. Querfeld C, et al. 2006 Ash Annual Meeting. Abstract 2732.
3. Querfeld C, et al. Leuk Lymphoma. 2009;50:1969-1976.
Start with skin care for SS patients
• Staph colonization induces pruritus, erythroderma, LDH, and elevated SS cells
– Oral dicloxicillin or IV vancomycin (MRSA)
– Bleach baths & antibacterial soap or
– Acetic acid rinse to lower pH
– Mupiricin for nares, fissures
• Repair barrier: Ceravé, Cetaphil, Restoraderm
• Topical triamcinolone with wet wraps
• Pruritus: Gabapentin 300 mg TID