Immunotherapy of Prostate Cancer

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Willis Bell
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1 Immunotherapy of Prostate Cancer Robert E. Reiter MD MBA Bing Professor of Urologic Oncology Geffen School of Medicine at UCLA

2 Costimulatory expression required for T cell activation

3 Therapeutic Vaccines in Prostate Cancer

4 Sipuleucel-T (Provenge ) Dendritic Cell Vaccine 4 Leukapheresis ~ 40 hours Culture Antigen Loading Antigen Processing Dendritic cell Tumor specific antigen Precursor APC Antigen-loaded APC Infusion In vivo T cell activation T cells attack tumor cells Dendritic cell

5 Percent Survival IMPACT Overall Survival P = (Cox model) HR = [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. Schellhammer, Higano, Berger et al, AUA Annual Meeting 2009.

6 ProstVac In vivo poxviral-based (Vaccinia and Fowlpox) peptide vaccine Encodes PSA and three costimulatory molecules (B7.1, ICAM- 1, and LFA-3) Phase II study demonstrated robust immune response 57% of patients developed PSA reactive T cells 68% of patients developed T cell response to TAA (antigen spreading) Randomized Phase II study showed increased OS Phase III PROSPECT study accrued 1298 patients asymptomatic or minimally symptomatic CRPC ProstVac vs. ProstVac + GM-CSF vs. Placebo Primary endpoint OS

7 Randomized Phase II Study of ProstVac-- Progression Free Survival

8 Randomized Phase II Study of ProstVac Overall Survival

9 DCVAC/PCa Autologous mature dendritic cells pulsed with killed PSA expressing LNCaP cells Phase II study of DCVAC + local Inquinimod (Toll Receptor 7 agonist) + initial metronomic Cyclophosphamide and concurrent Docetaxel Survival of 19 mo vs predicted survival of 11 mo based on Halabi nomogram VIABLE Phase III study of Docetaxel + DCVAC vs. Docetaxel + Placebo in metastatic CRPC

11 Checkpoint Inhibitors Definition molecules expressed on T cells and/or tumor cells that modulate T cell responses (off-signal) Tumor cells can evade immune system by expressing checkpoint inhibitors such as PDL1 CTLA-4 Checkpoint inhibitor expressed on T cells that limits T cell activation PD-1, PD-L1 Receptor and Ligands present on T cells and tumor cells Interaction limits T cell activation Additional Checkpoint Inhibitors LAG-3 TIM-3 VISTA

12 Checkpoint Inhibition Another Hurdle for Effective T cell Response in Cancer

13 PD-1-PDL1 interaction

14 Checkpoint Inhibitor in Prostate Cancer CTLA-4 Preclinical work in TRAMP and other models established potential Two Phase III studies completed Ipilumumab vs placebo in CRPC Negative for OS, not yet published Ipilumumab + low dose radiation in post-docetaxel CRPC Negative for PFS and OS Post-hoc analyses suggest areas for further exploration PD1, PDL1 No responses seen in Phase 1/II studies No or low level expression of PDL1 in prostate cancer Further studies needed to determine ways to induce PDL1 expression

15 Phase III Ipilumumab + Radiation vs Radiation in CRPC Post Docetaxel

16 Overall Survival Analysis Post-Chemo Ipilumumab Trial

17 Patient Subgroup Analysis Favors Bone Only and Good Performance Status

18 Post-Hoc Analysis Bone vs. Visceral

19 The Future of Checkpoint Inhibitor Therapy Creating an Immunogenic Tumor Microenvironment Vaccines + Checkpoint Inhibition Combinations with Chemotherapy/Hormonal Therapy/Radiation Therapy Cytokine or other Inducers of Checkpoint Inhibition

20 Chimeric T Cell Receptor Therapy Redirect T cells to tumor by engineering them to express a chimeric receptor encoding a tumor antigen ligand (usually an scfv fragment) Preconditioning of patients to ablate normal T cells Reconstitution of immune system by adoptive transfer of chimeric T cells

21 Structure of CAR T cells MHC Restricted MHC Unrestricted

22 CAR T Cell Structure

23 CAR T Cell Therapy

24 CAR-T Cell Toxicity Cytokine release storm Macrophage activation syndrome On-target, off-tissue toxicity Normal tissue expression of even low levels of ligand May limit with use of inducible/repressible CAR-T cells, dual receptor T cell constructs (e.g. PSMA/PSCA), suicide vectors

25 CAR-T Cell Therapy in Prostate Cancer Preclinical studies only to date PSCA PSMA Dual PSCA-PSMA Her-2/Neu

26 PSCA Directed CAR T Cells Abate-Daga et al. Human Gene Therapy 2014

27 Dual PSCA-PSMA CAR T Cell Kloss et al Nature Biotech 2013

28 Next generation TCR-Engineered T Cells

PROSPECT: A Randomized, Double-blind, Global Phase 3 Efficacy Trial of PROSTVAC-VF in Men with Metastatic Castration-Resistant Prostate Cancer

PROSPECT: A Randomized, Double-blind, Global Phase 3 Efficacy Trial of PROSTVAC-VF in Men with Metastatic Castration-Resistant Prostate Cancer James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials