Udai Kammula, MD, FACS presents Immunotherapy for Uveal Melanoma at the 2017 CURE OM Patient & Caregiver Symposium.

1. Immunotherapy for
Metastatic Uveal Melanoma
Udai S. Kammula, M.D., F.A.C.S.
Surgery Branch
National Cancer Institute
National Institutes of Health

2. 20142013
Cancer Immunotherapy

3. • 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?

4. Nature reviews 2004
Innate Immunity
(Rapid Response)
Adaptive Immunity
(Slow Response)
Components of the Immune System

5. Tumor Specific T Cells

6. Proliferation: Cytokines
Activate (release inhibition): Checkpoint
Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit
Endogenous Tumor Specific T Cells

7. Proliferation: Cytokines
Activate (release inhibition): Checkpoint
Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit
Endogenous Tumor Specific T Cells

8. Proliferation: Cytokines
Activate (release inhibition): Checkpoint
Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit
Endogenous Tumor Specific T Cells

9. Year Author Trial Type Therapy Criteria n PR CR ORR
(%)
2011 Tarhini Phase II Tremelimumab 15mg/kg RECIST 8 0 1 13
2012 Danielli EAP Ipilimumab 10mg/kg mod WHO 9 0 0 0
2013 Luke EAP Ipilimumab 3 or 10mg/kg
irRC and
mod WHO 35 1 1 6
2013 Kelderman EAP Ipilimumab 3mg/kg
RECIST
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 0
2015 Zimmer Phase II Ipilimumab 3mg/kg RECIST 34 0 0 0
2014 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/kg
RECIST
and irRC 25 2 0 8
2016 Algazi NA
Anti-PD-1 or Anti-PD-L1
(various doses) RECIST 56 2 0 4
TOTAL 291 12 3 5%
Checkpoint Blockade in Uveal Melanoma

10. Agents Phase Mechanism of action Trial ID
Selumetinib + MEDI4736 I MEKi + anti-PD-L1 NCT02586987
Nivolumab + ipilimumab II Anti-PD-1 + anti-CTLA-4
NCT01585194,
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 TCRs
NCT02570308
NCT02889861
Checkpoint Combinations and Others

11. Proliferation: Cytokines
Activate (release inhibition): Checkpoint
Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit
Endogenous Tumor Specific T Cells

12. Adoptive Cell Transfer (ACT) with TIL

13.  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
PBLTIL
Infusion
Surgery Branch/NCI
Adoptive TIL Transfer Therapy

14. n PR (%) CR (%) ORR (%)
194 62 (32%) 44 (23%) 106 (55%)
Adoptive TIL Transfer Therapy for Metastatic
Cutaneous Melanoma: Surgery Branch/NIH

15. Establish and Screen
TIL cultures for Tumor Reactivity
NCT01814046: Adoptive Immunotherapy for
Metastatic Uveal Melanoma--Trial Design
Expansion of Tumor Reactive
UM Specific TIL
Adoptive Transfer of Tumor
Reactive UM Specific TIL

16. Eligible and Consented
for Metastasectomy
(n=28)
Successful TIL expansion
for 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%)

17. NCT01814046: Demographics of UM Patients
Receiving Adoptive TIL Therapy
Number of patients 21
Age (mean; range) 52; 32-63
Gender F:M 8:13
Primary Tumor Treatment
RT 15 (71%)
Enucleation 6 (29%)
Metastatic Sites
Liver 20 (95%)
Extrahepatic 17 (81%)
AJCC M stage (Uveal criteria)
M1a 3 (14%)
M1b 10 (48%)
M1c 8 (38%)

18. 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%)

19. 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

20. Event n %
Lymphopenia 21 100
Neutropenia 21 100
Thrombocytopenia 21 100
Anemia 14 67
Infection 6 29
Treatment related death 1 5
Adverse Events (Grade >3)
Chemotherapy Related
No significant immune related adverse events

21. Best Overall Response to TIL Therapy in
Metastatic Uveal Melanoma
20 evaluable patients
ORR 7/20 (35%)
6 PR / 1 CR

22. 52 F with metastatic uveal
melanoma to liver, bone,
peritoneum
Presented with rapidly
deteriorating performance
Abdominal pain
Early satiety
Ascites
Weight loss
Bone pain
Narcotic use
UM Patient #10

23. Baseline
UM Patient #10

24. Baseline Post ACT +1 month
UM Patient #10

25. Pre
Tumor Regression in UM Patient #10
After TIL Therapy
Normal
cardiac
uptake
*

26. Tumor Regression in UM Patient #21
After TIL Therapy (checkpoint refractory)
Pre 1 month 2 months

27. Tumor Regression in UM Patient #21
After TIL Therapy (checkpoint refractory)
Pre 1 month 2 months

28. Patient 1
Pre TIL
5 months
Tumor Regression in UM Patient #1
After TIL Therapy (checkpoint refractory)

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

30. Pre TIL 21 months
Complete Regression in UM Patient #16
After TIL Therapy (checkpoint refractory)

31. Complete Regression in UM Patient #16
After TIL Therapy (checkpoint refractory)Tumorsize(cm
2
)
Time relative to TIL therapy (months)
Post anti-
CTLA-4/PD-1
TIL
Infusion
Liver met #1
Liver met #2

32. Kinetics of Tumor Response in
Uveal Melanoma Patients After TIL Therapy

33.  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

34. 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?

35. Genetic Engineering of T Cells to Target
Uveal Melanoma

36. NIH Pathology
Mark Raffeld
Liqiang Xi
Trinh Pham
CCR Bioinformatics
Eric Stahlberg
Parthav Jailwala
Yvonne Edwards
Acknowledgments
Kammula Lab
Smita Chandran
Arvind Sabesan
Biman Paria
Abhishek Srivastava
Luke Rothermel
Dan Stephens
Syed Shah
Anran Wang
Surgery Branch (SB)
Anna Pasetto
Todd Prickett
Jared Gartner
SB Cell Production
Facility
Rob Somerville
John Wunderlich
Immunotherapy Team
Marie Statler
Immuno Fellows
Immuno Senior Staff
Steven Rosenberg
Restifo Lab
Nick Restifo
Madhu Sukumar
SB Retroviral Core
Steve Feldman
University of Miami
J. William Harbour
Nicolas Acquavella
UM Patients and Families

37. Association Between Clinical Response and
Pre-treatment TIL Reactivity
Pre-treatment In Vitro Tumor Reactivity Criteria
> 3% frequency
> 2x109
cells
> 100 pg/ml IFN-γ
< 3% frequency
< 2x109
cells
< 100 pg/ml IFN-γ
P = 0.003