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