9-20-2014: Moffitt Cancer Center Presents NEW FRONTIERS IN UROLOGIC ONCOLOGY 8:20 – 8:40 am Immunotherapy for Prostate Cancer: Are We There Yet? Mayer Fishman, MD PhD Dept. of GU Oncology Member, Moffitt Cancer Center Dept of Oncologic Sciences Dept. of Internal Medicine Professor, University of South Florida Prostate cancer as an immune target • Unique antigens – PSA – PAP – PSMA • Long latency between presentation and escape • High local tumor: distant tumor ratio • Many patients • Favorable effects of low T on the thymus Dimensions for therapeutic modulation in cancer treatment (1) Antigens DC: Ex vivo loading Provenge DC: In vivo antigen provision Modulation of DC phenotype: Viruses Cofactors: GM-CSF, CD40L, ATRA Dimensions for therapeutic modulation in cancer treatment (2) Lymphocytes Phenotype modulation/checkpoint inhibition: CTLA-4 PD-1 PDL1 KIR Ex vivo manipulation & re-infusion: CAR T cells Lymphocytes – activation Sipuleucel-T Sipuleucel-T How it is supposed to work In vivo antigen presentation &amplification of lymphocyte response Processing At Dendreon Reinfusion of activated APC & lymphocytes More immune amplification Lymphocyte homing to and 3 cycleskilling of tumor cells Tumor Sipuleucel-T controversies Kantof et al. Huber et al. [Standard sipuleucel-T]  chase with new intervention Building on sipuleucel-T 1999 Sipuleucel-T Sipuleucel-T and another immune modulation Building on sipuleucel-T: some open studies Coordinated with hormone therapy: GnRH agonist Abiraterone Enzalutamide Clinicaltrials.gov Searched 9-9-14 Coordinated with radiotherapy Coordinated with vaccination; pTVG-HP (DNA for PAP) Coordinated with lymphocyte modulators: anti PD-1 & cyclophosphamide CTLA-blockade IL-7 Coordinated DC modulation Indoximod (IDO inhibitor) tasquinimod (TLR4 agonist & other S100A9 effects) Radiation as immunotherapy A conventional view of XRT cumulative DNA lesions Apoptosis A conventional view of XRT cumulative DNA lesions Apoptosis protein & DNA changes Necrosis Differential sensitivity of tissues Differential sensitivity of tissues Stroma Tumor Tumor  immune interactions Lymphocytes NK T-reg T cd8+ B T cd4+ granulocytes Eos Neut Bas Antigen presenting cells DC MDSC MФ What effect on the immune system? Lymphocytes +T-reg NK - T cd8+ B T cd4+ granulocytes Eos Neut Bas Antigen presenting cells - DC + MDSC MФ After irradiation? Lymphocytes +T-reg NK - T cd8+ B T cd4+ granulocytes Eos Neut Bas Antigen presenting cells - DC + MDSC MФ Immune reaction after irradiation Lymphocytes NK T cd8+ T-reg B MDSC T-reg T cd8+ T cd4+ granulocytes DC NK T cd8+ Eos Neut Bas Antigen presenting cells DC MDSC MФ Differential sensitivity of tissues Including the immune compartment Lymphocytes Dendritic cells and macrophages Apoptosis Phenotype alteration Tumor cells Apoptosis Changes of NK, T, B relative number Apoptosis & Necrosis. Antigen expression Stroma and endothelium Hypoxia & Inflammation Multiple interactions cartoon Lymphocytes Dendritic cells and macrophages Tumor cells Antigen provision Signals mediating change to an activated antigen presentation phenotype Stroma and endothelium Multiple interactions cartoon Antigen presentation Costimulation Dendritic cells and macrophages Lymphocytes CXCL16 Tumor cells Stroma and endothelium Multiple interactions cartoon CTL & NK effector mediated killing Lymphocytes Dendritic cells and macrophages Tumor cells Leukocyte infiltration Stroma and endothelium Comprehensive interaction cartoon Antigen presentation CTL & NK effector mediated killing Leukocyte infiltration Costimulation Dendritic cells and macrophages Lymphocytes CXCL16 Antigen provision Signals mediating change to an activated antigen presentation phenotype Tumor cells Stroma and endothelium Radiation & DC a (sort of old) pilot project Immune effects of radiation Energy-ablative local therapy Tolerogenic Killed tumor tumor Energy-ablative local therapy Tolerogenic Killed tumor Inflammation tumor DC Micrometastases unscathed Radiation therapy of localized, but high-risk prostate cancer is an ideal platform for application of immunemediated innovations: • Microscopic distant burden • Well-defined tumor antigens to monitor immune response •Usual local success of definitive-intent local therapy Micrometastases impacted by abscopal effect Murine model – XRT & intratumoral DC C3 tumor model system 3 fraction of subcurative 10 Gy Syngeneic DC injections into the tumor Intraprostatic DC injection and radiation therapy Day 15 biopsy evalu CD4 Elispot for HLA*0201-associated test peptides CD8 Cleaved caspase (apoptosis): in situ tumor destruction & lymphocytes –checkpoint inhibition 1. 2. 3. 4. Establish (L) x28 days Cryo (L), then next day: Challenge (R), ±anti CTLA-4 Follow size on (R) Tetramerpositive CD8+ TIL with specificity for the TRAMP C2 antigen SPAS-1 Tetramerpositive CD8+ splenocytes, with specificity for the TRAMP C2 antigen SPAS-1 Ipilimumab versus placebo after RT in mCRPC after docetaxel 399 Ipilumimab Q3w x4 8 Gy x 1 400 * Placebo Q3w x4 Median OS [95% CI] 11·2 months (9·5-12·7) 10·0 months (8·3-11·0) HR = 0·85 (0·72-1·00) 4 toxic deaths p=0·053 The proportional hazards assumption was violated (p=0·0031): HR 0-5 m= 1·46 (CI 1·10-1·95) HR 5-12 m = 0·65 (0·50-0·85) HR > 12+ =0·60 (0·43-0·86) favors PLACEBO favors ipilumimab favors ipilumimab Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR; CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):700-12 Ipilimumab versus placebo after RT in mCRPC after docetaxel Selected retrospective subsets – an hypothesis generating exercise. Chuck Drake The best patients for this treatment may be those with: • ALP < 1.5 xUL, • LDH < 2x ULN, • Hgb > 11 • no visceral mets Viral antigen & adjvuant delivery PROSTVAC: immunologic PROSTVAC: clinical PROSTvac & enzalutamide trial NCT01867333: Enzalutamide With or Without Vaccine Therapy for Advanced Prostate Cancer Enzalutamide Ongoing Accrual Phase II Enzalutamide PROSTVAC/V PROSTVAC: PROSTVAC/F PSA TRICOM = B7.1, leukocyte function-associated antigen-3 (LFA-3) intercellular adhesion molecule-1 (ICAM-1) Priming: PROSTVAC/V = vaccinia Monthly boost: PROSTVAC/F = fowlpox No data yet Tasquinimod –Is it immunologic? –Is it antiangiogenic? –Does it modulate AR? T A S Q U I N I M O D Mechanism of action IMMUNOTHERAPY: MDSC ANGIOGENESIS IMMUNOTHERAPY: TAM T A S Q U I N I M O D Mechanism of action Does this work? mCRPC Asymptomatic or minimally symptomatic Placebo to 6m 67 134 .25/d x 2w Primary endpoint: Median PFS: .50/d x 2w Crossover at PD or at 6 months 1.0/d to 6m Continue open label 7.6 vs 3.3 months P = 0.0042; HR, 0.57 (0.39–0.85)] Secondary endpoint: Median OS 33.4 vs 30.4 months HR= 0.87 (0.59–1.29) Those who got TASQ, up front, or at crossover did better Immunotherapy for Prostate Cancer: Are We There Yet? 8:40 am So. Are we there yet? Would a generic graphic clinch it? Forward looking conclusions Coordinated use of radiation Amplification of sipuleucel-T effect PROSTVAC/VF trials Immune micronenvironment of local ablation Checkpoint inhibitor trials – throughout oncology • Tasquinimod – not unsafe • • • • •