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Immunotherapy for Uveal Melanoma - Udai Kammula, MD, FACS

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

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Immunotherapy for Uveal Melanoma - Udai Kammula, MD, FACS

  1. 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. 2. 20142013 Cancer Immunotherapy
  3. 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. 4. Nature reviews 2004 Innate Immunity (Rapid Response) Adaptive Immunity (Slow Response) Components of the Immune System
  5. 5. Tumor Specific T Cells
  6. 6. Proliferation: Cytokines Activate (release inhibition): Checkpoint Blockade Adoptive transfer: Autologous TIL Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
  7. 7. Proliferation: Cytokines Activate (release inhibition): Checkpoint Blockade Adoptive transfer: Autologous TIL Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
  8. 8. Proliferation: Cytokines Activate (release inhibition): Checkpoint Blockade Adoptive transfer: Autologous TIL Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
  9. 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. 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. 11. Proliferation: Cytokines Activate (release inhibition): Checkpoint Blockade Adoptive transfer: Autologous TIL Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
  12. 12. Adoptive Cell Transfer (ACT) with TIL
  13. 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. 14. n PR (%) CR (%) ORR (%) 194 62 (32%) 44 (23%) 106 (55%) Adoptive TIL Transfer Therapy for Metastatic Cutaneous Melanoma: Surgery Branch/NIH
  15. 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. 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. 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. 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. 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. 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. 21. Best Overall Response to TIL Therapy in Metastatic Uveal Melanoma 20 evaluable patients ORR 7/20 (35%) 6 PR / 1 CR
  22. 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. 23. Baseline UM Patient #10
  24. 24. Baseline Post ACT +1 month UM Patient #10
  25. 25. Pre Tumor Regression in UM Patient #10 After TIL Therapy Normal cardiac uptake *
  26. 26. Tumor Regression in UM Patient #21 After TIL Therapy (checkpoint refractory) Pre 1 month 2 months
  27. 27. Tumor Regression in UM Patient #21 After TIL Therapy (checkpoint refractory) Pre 1 month 2 months
  28. 28. Patient 1 Pre TIL 5 months Tumor Regression in UM Patient #1 After TIL Therapy (checkpoint refractory)
  29. 29. Pre TIL Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)
  30. 30. Pre TIL 21 months Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)
  31. 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. 32. Kinetics of Tumor Response in Uveal Melanoma Patients After TIL Therapy
  33. 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. 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. 35. Genetic Engineering of T Cells to Target Uveal Melanoma
  36. 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. 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

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