Is Prostate Cancer Amenable to Immunotherapy Approaches? New Frontiers in Urologic Oncology, September 12, 2015

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1 Is Prostate Cancer Amenable to Immunotherapy Approaches? New Frontiers in Urologic Oncology, September 12, 2015 J. J. Mulé Associate Center Director, Translational Research U.S. Senator Connie Mack & Family Chair, Melanoma Research and Treatment Moffitt Cancer Center

2 Disclosures Celgene Corp. (Business Strategy Advisory Board) Etubics Corp. (SAB) Kite Pharma, Inc. (Consultant) Lion Biotechnologies (SAB) Lycera Corporation (SAB) OncoPep, Inc. (SAB) Oxis Biotechnologies, Inc. (SAB) Select Bioventures (Advisory Board) Vault Nano, Inc. (SAB)

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4 Immunotherapy for Solid Tumors: Basic Requirements for Successful Clinical Response 1. Immune T cell infiltration into the tumor mass: More is better 2. Gene mutation load: More is better (creation of foreign neoantigens)

5 Immunotherapy for Solid Tumors: Basic Requirements for Successful Clinical Response Immune T cell infiltration into the tumor mass: More is better

6 Adoptive T Cell Transfer Tumor Infiltrating Lymphocytes (TIL)

7 Tumor-Infiltrating Lymphocytes (TIL) for Treatment of Metastatic Melanoma

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11 Rapid Expansion Billion TIL

12 Examples of Clinical Response to Adoptive Cell Therapy in Advanced Melanoma

13 Response of a Brain Metastasis to TIL Therapy

14 . Response of Liver Metastases to TIL Therapy

15 Rosenberg, S.A. et al CCR 2012

16 Immune gene expression signature (GES) in solid tumors: The haves and the have nots Messina et al. Nature Sci. Rep. (nature.com) Green: negative for GES Red: positive for GES

17 Variation in lymphoid infiltrates observed in human cancer Immune Gene Signature - Immune Gene Signature + B cells T cells None Ectopic follicle B cells Capsule T cells Dispersed Ectopic follicle with capsule

18 Ectopic Lymph Node Structures in a Solid Tumor with Adjacent Tumor Destruction

19 12-Chemokine GES Identifies Stage IV Melanoma Patients with Better Overall Survival Percent survival p<0.0001

20 Interrogation of an Immune Gene Expression Signature across 8,674 Solid Tumors of Differing Histology: TCGA Database

21 Immunotherapy for Solid Tumors: Basic Requirements for Successful Clinical Response Gene mutation load: More is better (creation of foreign neoantigens)

22 Gene Mutation Load vs. Human Tumor Type Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-8

23 Checkpoint proteins and their ligands Int. Immunol. 19 (7):

24 Ipilimumab enhances TIL infiltration Immunohistochemistry (IHC) of TIL Ipilimumab prior to TIL harvest may increase the number of TIL that are infused. Provide disease control and decrease patient drop out rates prior to TIL transfer.

25 Epigenetic drug treatment of tumor cells can dramatically enhance the expression of a ~300 gene immune pathway response signature

26 Epigenetic drug treatment upregulates, in tumor cells, (red circles) immunogenic signals, including the immune tolerance ligand PD-L1, antigens on the cell surface (tumor-associated antigens and MHC class 1, interferon driven signaling, etc. Yellow arrows show target step for anti-pd-1 antibody (Nivolumab)

27 A Snapshot of Immunotherapy Trials for Prostate Cancer Type Agent Phase ClinicalTrials.gov Therapeutic Vaccines Sipuleucel-T (Provenge) Approved Prostvac II NCT Sipuleucel-T +/- ptvg-hp DNA (booster) II NCT Sipuleucel-T ptvg-hp DNA alone II NCT Autologous dendritic cells/tarp II NCT Autologous dendritic cells/prostate cell lines II NCT PSA vaccine after local therapy II NCT Oncolytic Virus ProstAtak + radiation (localized) III NCT Checkpoint Inhibitors Ipilimumab (anti-ctla-4; Yervoy) + Provenge Source: Cancer Research Institute II NCT Ipilimumab alone + hormone therapy II NCT

28 A Snapshot of Immunotherapy Trials for Prostate Cancer (continued) Type Agent Phase ClinicalTrials.gov Checkpoint Inhibitors Ipilimumab plus androgen suppression therapy II NCT Ipilimumab plus degarelix II NCT Pembrolizumab (anti-pd-1; Keytruda Merck) previously treated with enzalutamide Atezolizumab (anti-pd-l1; MPDL 3280A Genentech/Roche) II II NCT NCT Sipuleucel-T, CT-011 (CureTech), Cy II NCT Adoptive Cells CAR-T: NYESO-1 II NCT CAR-T: NYESO-1 + dendritic cells/nyeso-1 II NCT Adjuvants Sipuleucel-T + inodoximad (IDO inhibitor) II NCT Source: Cancer Research Institute

29 Jonathan W. Simons Cancer Immunol Res 2014;2: by American Association for Cancer Research

30 References Boussiotis, V.A.: Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma. N. Engl. J. Med. 371: , Messina, J.L., Fenstermacher, D.A., Eschrich, S., Qu, X., Berglund, A.E., Lloyd, M.C., Schell, M.J., Sondak, V.K., Weber, J.S., and Mulé, J.J.: 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Nature - Scientific Reports (nature.com) 2: , Weber, J.: Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade. Semin. Oncol. 37: , 2010.

31 Foundation Support and Industry Alliances