Immunotherapy for Metastatic Uveal Melanoma

Udai S. Kammula, M.D., F.A.C.S.Surgery Branch

National Cancer InstituteNational Institutes of Health

20142013

Cancer Immunotherapy

• A type of cancer treatment designed to boost the body's natural defenses to fight the cancer.

• It uses substances either made by the body or in a laboratory to improve or restore immune system function.

What is Cancer Immunotherapy?

Nature reviews 2004

Innate Immunity(Rapid Response)

Adaptive Immunity(Slow Response)

Components of the Immune System

Tumor Specific T Cells

Proliferation: Cytokines

Activate (release inhibition): Checkpoint Blockade

Adoptive transfer: Autologous TIL

Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells

Proliferation: Cytokines

Activate (release inhibition): Checkpoint Blockade

Adoptive transfer: Autologous TIL

Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells

Proliferation: Cytokines

Activate (release inhibition): Checkpoint Blockade

Adoptive transfer: Autologous TIL

Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells

Year Author Trial Type Therapy Criteria n PR CR ORR(%)

2011 Tarhini Phase II Tremelimumab 15mg/kg RECIST 8 0 1 132012 Danielli EAP Ipilimumab 10mg/kg mod WHO 9 0 0 0

2013 Luke EAP Ipilimumab 3 or 10mg/kgirRC and

mod WHO 35 1 1 6

2013 Kelderman EAP Ipilimumab 3mg/kgRECIST and irRC 14 1 0 7

2013 Khattak EAP Ipilimumab 3mg/kg RECIST 5 0 0 0

2013 Maio EAP Ipilimumab 3mg/kg irRC 82 4 0 5

2015 Joshua Phase II Tremelimumab 15mg/kg RECIST 11 0 0 02015 Zimmer Phase II Ipilimumab 3mg/kg RECIST 34 0 0 02014 Herbst NA MPDL-3280A (Anti-PD-L1) RECIST 4 0 0 0

2016 Kottschade EAP Pembrolizumab 2mg/kg irRC 8 2 1 38

2016 Karydis EAP Pembrolizumab 2mg/kgRECIST and irRC 25 2 0 8

2016 Algazi NAAnti-PD-1 or Anti-PD-L1

(various doses) RECIST 56 2 0 4  TOTAL  291 12 3 5%

Checkpoint Blockade in Uveal Melanoma

Agents Phase Mechanism of action Trial ID

Selumetinib + MEDI4736 I MEKi + anti-PD-L1 NCT02586987

Nivolumab + ipilimumab II Anti-PD-1 + anti-CTLA-4NCT01585194, NCT02626962

Indoximod+ pembrolizumab/

nivolumab/ipilimumab I/II IDO inhib + checkpoint NCT02073123

Pembrolizumab + Entinostat II HDAC inhib + checkpoint NCT02697630

Nivolumab + anti-CD137 +TIL I

TIL + checkpoint + agonistic CD137 ab NCT02652455

IMCgp100 I/II Immune mobilizing TCRsNCT02570308NCT02889861

Checkpoint Combinations and Others

Proliferation: Cytokines

Activate (release inhibition): Checkpoint Blockade

Adoptive transfer: Autologous TIL

Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells

Adoptive Cell Transfer (ACT) with TIL

Non-myeloablative (NMA) lymphocyte depleting preparative regimen:

Cyclophosphamide (60 mg/kg/day X 2 days IV) Fludarabine (25 mg/m2/day IV X 5 days)

Intravenous infusion of TIL

High-dose intravenous (IV) IL-2

DAY -7 -5

Cy Fludarabine IL-2

TIL infusion

0

PBLTIL Infusion

Surgery Branch/NCI Adoptive TIL Transfer Therapy

n PR (%) CR (%) ORR (%)

194 62 (32%) 44 (23%) 106 (55%)

Adoptive TIL Transfer Therapy for Metastatic Cutaneous Melanoma: Surgery Branch/NIH

Liver Tumor Resection

Adoptive Transfer ofAutoreactive OM specific TIL

Expansion of Autoreactive OM specific TIL

1

2

3Tumor Exome Sequencingto Identify Driver Mutations

Establish and Screen TIL cultures for Tumor Reactivity

NCT01814046: Adoptive Immunotherapy for Metastatic Uveal Melanoma--Trial Design

Expansion of Tumor ReactiveUM Specific TIL

Adoptive Transfer of Tumor Reactive UM Specific TIL

Eligible and Consented for Metastasectomy

(n=28)

Successful TIL expansionfor potential therapy

(n=27; 96%)

Insufficient TIL expansion (n=1)

No TIL identified in tumor after prior Yttrium bead therapy

NCT01814046: Generation of TIL from Uveal Melanoma Metastases

Underwent Successful Metastasectomy(n=28)

Liver procurement (61%)

NCT01814046: Demographics of UM Patients Receiving Adoptive TIL Therapy

Number of patients 21Age (mean; range) 52; 32-63

Gender F:M 8:13

Primary Tumor TreatmentRT 15 (71%)

Enucleation 6 (29%)

Metastatic SitesLiver 20 (95%)

Extrahepatic 17 (81%)

AJCC M stage (Uveal criteria)M1a 3 (14%)M1b 10 (48%)M1c 8 (38%)

NCT01814046: Demographics of UM Patients Receiving Adoptive TIL Therapy

Prior Response

0/12

Number of patients 21

Prior systemic therapy 12 (57%)

Prior immunotherapy 9 (43%)Anti-CTLA-4 only 1 (5%)

Anti-PD-1 only 1 (5%)Anti-CTLA-4 + Anti-PD-1 7 (33%)

Number of patients 21

Cyclophosphamide (60 mg/kg/day X 2 days IV)Fludarabine (25 mg/m2/day IV X 5 days) All

Total cells (x109), median (range) 85 (17-138)% CD4+, median (range) 60% (2-95%)% CD8+, median (range) 39% (2-98%)

IL-2 doses, median (range) 5 (0-8)

NCT01814046: Treatment of UM Patients with Adoptive TIL Therapy

Event n %Lymphopenia 21 100Neutropenia 21 100

Thrombocytopenia 21 100Anemia 14 67Infection 6 29

Treatment related death 1 5

Adverse Events (Grade >3)

Chemotherapy RelatedNo significant immune related adverse events

9 19 5 13 1 8 4 12 6 18 3 17 2 15 10 14 20 21 11 16-100

-50

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Max

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919513184126183172201510141116 -100

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0

50

1005

16

Checkpoint refractoryNo prior checkpoint

Prior Immunotherapy

++

+

Best Overall Response to TIL Therapy in Metastatic Uveal Melanoma

20 evaluable patientsORR 7/20 (35%)

6 PR / 1 CR

52 F with metastatic uveal melanoma to liver, bone, peritoneum

Presented with rapidly deteriorating performanceAbdominal painEarly satietyAscitesWeight lossBone painNarcotic use

UM Patient #10

Baseline

UM Patient #10

Baseline Post ACT +1 month

UM Patient #10

Patient 12 Pre TIL 2 months1 month 3 months

PerOm

Liv

Bo Bo

Bo

Bo

PerOm

Bo

*

*

*

*

Pre

Tumor Regression in UM Patient #10 After TIL Therapy

Normalcardiacuptake

*

Tumor Regression in UM Patient #21 After TIL Therapy (checkpoint refractory)

Pre 1 month 2 months

Tumor Regression in UM Patient #21 After TIL Therapy (checkpoint refractory)

Pre 1 month 2 months

Pre Post 5 months Pre Post 5 months Pre Post 5 months

Pre Post 5 months Pre Post 5 months Pre Post 5 months

Patient 1Pre TIL

5 months

Tumor Regression in UM Patient #1 After TIL Therapy (checkpoint refractory)

Pre TIL

Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)

Pre TIL 21 months

Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)

Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)

0

5

10

15

20

-10 -5 0 5 10 15 20

Series1

Series20

5

10

15

20

-9-6-30369

Series1

Series2

Tum

or s

ize

(cm

2 )

Time relative to TIL therapy (months)

Post anti-CTLA-4/PD-1

TILInfusion

Liver met #1

Liver met #2

Data 1

0 5 10 15 20-100-80-60-40-20

020406080

100

Caruso 1TourignyParkerWinningScott

ChoateGuarinoProto, Michael

Warner, Ingemar

Dillon, John

Deschryver, Michelle

Begnaud, Lynn

Reichlin, Richard

Sandner, Kirsten

Dschuhan, Patricia

Chamberlain

white

McNeight

Bussman1

harrer

Cha

nge

in tu

mor

size

from

bas

elin

e (%

)

Time since TIL therapy (months)

PD (20% increase)

PD (New lesion)

Ongoing

Checkpoint refractoryNo prior checkpoint

Prior Immunotherapy Current response status

Kinetics of Tumor Response in Uveal Melanoma Patients After TIL Therapy

Selected metastatic uveal melanoma patients are responsive to TIL immunotherapy.

Durable complete regression can be achieved in metastatic uveal melanoma.

Clinical response correlates with the autologous tumor reactivity of the infused TIL

Summary

Limitations of Current Study and Unanswered Questions

Small pilot trial

Highly selected patients enrolled

Need more data to determine: Which patients will benefit? Durability of responses? How to improve the T cell product?

How can we help patients who don’t have reactive T cells in their TIL?

Genetic Engineering of T Cells to Target Uveal Melanoma

NIH PathologyMark RaffeldLiqiang XiTrinh Pham

CCR BioinformaticsEric StahlbergParthav JailwalaYvonne Edwards

AcknowledgmentsKammula LabSmita ChandranArvind SabesanBiman PariaAbhishek SrivastavaLuke RothermelDan StephensSyed ShahAnran Wang

Surgery Branch (SB)Anna PasettoTodd PrickettJared Gartner

SB Cell Production FacilityRob SomervilleJohn Wunderlich

Immunotherapy TeamMarie StatlerImmuno FellowsImmuno Senior StaffSteven Rosenberg

Restifo LabNick RestifoMadhu Sukumar

SB Retroviral CoreSteve Feldman

University of Miami J. William HarbourNicolas Acquavella

UM Patients and Families

Association Between Clinical Response and Pre-treatment TIL Reactivity

Pre-treatment In Vitro Tumor Reactivity Criteria

> 3% frequency> 2x109 cells> 100 pg/ml IFN-

< 3% frequency< 2x109 cells< 100 pg/ml IFN-

P = 0.003

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Num

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R NR

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Response vs. Frequency of Tumor Reactive TILs

Response vs. Number of Tumor Reactive TILs

A. B.

R NR

Response vs. IFN- release from Tumor Reactive TILs

C.

P = .01 P = .008 P = .006