Fifteenth International Kidney Cancer Symposium

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1 The following presentation should not be regarded as an endorsement of a particular product/drug/technique by the speaker. The presentation topics were assigned to the speakers by the scientific committee of the KCA, to be presented/interpreted as part of a comprehensive scientific debate. Therefore, this presentation should not be viewed/interpreted in isolation, and should be considered in context with the other presentations in the same session. " Fifteenth International Kidney Cancer Symposium November 4-5, 2016 Marriott Miami Biscayne Bay, Miami, Florida, USA

2 To Combine or Sequence: Biological Rationale Charles G. Drake MD / PhD Director GU Medical Oncology Co-Director Immunotherapy Program Associate Director for Clinical Research Herbert Irving Cancer Center at Columbia University

3 Disclosure Consultant / Advisor: Agenus, Compugen, Dendreon, NexImmune, Novartis, ImmunExcite, Janssen, Lilly, Merck, Pierre Fabre, Potenza, Roche / Genentech, Tizona Sponsored Research Agreement: Aduro Biotech, Bristol Myers Squibb, Compugen, Janssen Ownership / Patents: AZ Medimmune, Bristol Myers Squibb, Compugen, Potenza I will discuss off label use and/or investigational use in my presentation

4 Drake CG Seminars Oncology 2015 Let Me Count the Ways..

5 Outline Combining PD-1 Blockade with Cancer Vaccines / RT Combining PD-1 Blockade with Blockade of Additional Immune Checkpoints Combining VEGF-Blockade with PD-1 Blockade

6 PD-1 Blockade Functional During Initial Antigen Encounter (PD-1 Can NOT rescue truly exhausted CD8 T cells) Tolerogenic Antigen ReChallenge Block PD-1 or PD-L1 During Antigen Encounter Block PD-1 or PD-L1 Late Tsushima F et al. Blood 2007;110:

7 Combining PD-1 Blockade With Additional Checkpoints Is NOT the same as Sequencing.. (in mice) median tumor volume (mm3) CCCPPP PPPCCC CTLA-4 PD-1 combination days injected on d0 with 2 x 10 6 cells dosing 10 mg/kg or 10 mg/kg con Control 9D9 a CTLA-4 4H2 a PD-1 9D9+4H2 a PD-1 + a CTLA-4 CCCPPP PPPCCC Courtesy of A. Korman

8 Biological Rationale: Anti-PD-1 and Anti-CTLA-4 Act on Different Cell Types CD8 T cell Tumor Antigen TCR PD-1 MHC PD-L1 Tumor cell Regulatory CD4 T Cell (FoxP3+) CTLA CTLA Anti-CTLA PD-1 PD-L2 PD-L1 Expression on Tumor Cells OR Myeloid Cells SENDS that Negative Signal Supressive Factors CD8 T cell +++ TCR MHC Tumor cell

9 Alternative Scenario: PD-1 Blockade Causes Adaptive Up-Regulation Of Additional Checkpoint Molecules PD-1 Anti-PD-1 or Anti-PD-L1 PD-1 LAG-3 TIGIT Tim-3 CD8+ T cells CD8+ T cells

10 Potential Immunological Effects of VEGF Inhibition Normalize Tumor Vasculature -> Permit T Cell Immigration Into Tumor Bed VEGF Promotes Inhibitory Dendritic Cells / Myeloid Suppressor Cells Anti-Tumor Effects of VEGF Inhibition -> Immunogenic Cell Death

11 Immunological Activity of VEGF Blockade / TKI Normalize Tumor Vasculature -> Permit T Cell Immigration Into Tumor Bed SEQUENCE VEGF inhibition -> PD-1 Blockade

12 Immunological Activity of VEGF Blockade / TKI VEGF Promotes Inhibitory Dendritic Cells / MDSC COMBINE VEGF Blockade with PD-1 Blockade

13 Immunological Activity of VEGF Blockade / TKI Anti-Tumor Effects of VEGF Inhibition -> Immunogenic Cell Death Block PD-1 -> VEGF inhibition

14 Immunogenic Cell Death (including RT) PD-1 blockade in place during initial T cell expansion / antigen encounter Vaccines Same Combined Immunotherapy / Checkpoint Blockade Combined administration reasonable. Unless reflex up-regulation of additional checkpoints VEGF-inhibition Conclusion(s) Depends on immunological effects of VEGF inhibition in humans

15 Drake Laboratory (Alumni) Tullia Bruno Satoshi Wada Tim Harris Joe Grosso Monica Goldberg Nick Durham Chris Nirshl Andrew Sharabi Tina Ceccato Drake Laboratory (Current) Daisy Chen Chris Jackson Brian Francica Areli Lopez Allison Martin Ali Ghasmedzehah Areli Lopez Maria Carera Tom Nirschl Acknowledgements Urology Mo Allaf Mark Ball Mike Gorin Mike Johnson Phil Pierazio BMS Alan Korman Mark Selby Kent Thudium Nils Lonberg Maria Jure-Kunkel 043 ProstateTrial Win Gerritsen Howard Scher Eugene Kwon Patients and Families Pathology Angelo De Marzo Helen Fedor Alan Meeker Mike Haffner Funding Damon Runyon MRA NIH / NCI OneInSix PCF PCW Foundation Dept Urology BMS IIoN Slides / Collaboration David McDermott Hans Hammers Brian Rini