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Immunotherapy for Prostate Cancer: Are we on the right target?

Immunotherapy for Prostate Cancer: Are we on the right target?. Susan F. Slovin, MD, PhD Sidney Kimmel Center for Prostate and Urologic Cancers Memorial Sloan-Kettering Cancer Center New York, New York. Rationale for Vaccines in Prostate Cancer.

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Immunotherapy for Prostate Cancer: Are we on the right target?

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  1. Immunotherapy for Prostate Cancer:Are we on the right target? Susan F. Slovin, MD, PhD Sidney Kimmel Center for Prostate and Urologic Cancers Memorial Sloan-Kettering Cancer Center New York, New York

  2. Rationale for Vaccines in Prostate Cancer 1. Well-characterized glycoprotein and carbohydrate antigens: PSA, PSMA, PSCA, Globo H, GM2, MUC-1,2, Tn, TF, Lewisy. 2. Biomarker (PSA) available to study disease progression. 3. Can be used in all disease states: biochemical relapse thru castration resistant disease. 4. Can be potentiated via combinatorial approaches: chemotherapy, biologic agents (GM-CSF) or checkpoint inhibitors (anti-CTLA-4, anti-PD-1).

  3. Is there a “best” approach?

  4. A (very) brief history of cancer vaccines Whole cell or shed antigen Purified protein Peptide Where does immunotherapy end and vaccines begin?

  5. PSMA Expression on LNCaP Cell MoAbs Vaccines: DNA, alhydrogel, DG, VRP - T cell J415, J591 - ADCC Extracellular NH2... Intracellular MoAb 7E11 Antibody Drug Conjugate: auristatin maytansinoid ProstaScint Scan Cell membrane Modified from P. Smith-Jones 2004

  6. Results of Clinical Trial Endpoints • Tumor responds - target is hit • Tumor responds - target is missed • Tumor respond - target is hit • Tumor  respond - target is missed All say something about the biology of the tumor and how the therapy should be directed

  7. Immunotherapy / Vaccine Approaches in Development for Treatment of CRPC • Tumor antigen vaccines • Vaccinate patient with antigens that activate tumor-specific T-cell responses • Autologous dendritic cells (DCs) • GM-CSF; lenalidomide • Cytokines and DC stimulation • CTLA-4 (cytotoxic T-lymphocyte-associated antigen) blockade

  8. Ipilimumab • A fully human anti-CTLA-4 mAb (IgG1k) • Effectively blocks CTLA4–B7 interactions • Currently in Phase III trials and in first and second line melanoma • Survival benefit in patients with treated melanoma – phase III • Clinically significant and durable tumor regression in multiple tumors(melanoma, prostate, renal, ovarian,…) • Immune Related Responses can occur with initial progression followed by regression • Immune-related adverse events (irAE) • Likely mechanism based; consistent with enhanced activity of T cells due to the blockade of CTLA-4 function • Usually reversible and associated with clinical response in melanoma, renal cell, and prostate cancer

  9. IL-2 APC B7-1,2 CTLA-4 Blockade Enhances Tumor-Specific Immune Responses Attenuated or Terminated Proliferation Unrestrained Proliferation Tumor APC Necrotic Death Vaccines Chemotherapy Irradiation Hormone therapy Anti-angiogenesis CD28 CTLA-4 TCR Leach & Allison Science 1996 Peptide/MHC

  10. M.O.A. of CTLA-4 2 1 TCR + Ag on DC = Engagement Door to CTLA-4 activation is closed 5 3 4 Abort! “Go or No Go?”– Awaiting T cell activation or shutdown Full go !! T cell proliferation… or…

  11. Skin reactions at the GVAX injection sites GVAX IT + MDX-010 (0.3 mg/kg) GVAX IT + MDX-010 (3 mg/kg) After 1 week GVAX IT alone Injection site reactions were the most common adverse event (100%) No DLTs nor auto-immunity observed

  12. a : 13Mar06: SAE -Hypophysitis (7 mo) b: 03Feb06: Hypophysitis (5 mo) c: 09Feb06: SAE – Hypophysitis (5 mo) PSA curves – Dose Level 3 (3 mg/kg) Pt 7 Pt 8 a b c Pt 9 Gerritsen, ASCO 2006

  13. Patient 8 Bone Scan Improvement in Patient 8 (3 mg/kg) 29Mar06 15Sept05 Gerritsen ASCO2006

  14. Objective Tumor Response Patient 12 (5 mg/kg) 14Feb06 16May06 Gerritsen, ASCO 2006

  15. Immune Breakthrough Events (IBE) • No IBE in DL 1 and 2 • 5 of 6 patients in 3 mg/kg and 5 mg/kg with IBE • All associated with PSA response • All delayed • All endocrine-related & treatable with standard hormone replacement therapy

  16. Pathology of Autoimmune Breakthrough Events: Colitis D C Histopathologic analyses of selected patients experiencing autoimmune events. (C) Colon biopsy from Patient 9 illustrating severe colitis with infiltration of the lamina propria with neutrophils, lymphocytes, monocytes, plasmacytes and eosinophils. Neutrophils and lymphocytes also infiltrate the crypts; numerous mitotic figures can be seen in the epithelial cells lining the crypts (20X). Immunohistochemistry evaluating expression of CD3+ (D), CD4+ (E), and CD8+ markers (F) (20X). CD3 E F CD4 CD8 Source: Abstract #3424, ASCO 2003

  17. Rationale: Radiotherapy as an Immune-Supportive Intervention for CTLA-4 Blockade Anti-CTLA4 mAb CTLA-4 Anti-CTLA4 mAb CTLA-4 Modified after:Demaria, et al, Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 3, pp. 655–666, 2005

  18. Subject 3020, 10 mg/kg monotherapy Beer, et al, ASCO 2008

  19. Subject 3020:Resolution of Prostate Mass 14 months Screening

  20. Best PSA Changes: Each Subject XRT in NoCHEMO Mono XRT in CHEMO Slovin, et al, ASCO 2009)

  21. Time-to-Response and Durability of Confirmed PSA Response Time-to-Response (>50% decrease) Response Durability *: PSA CR **: Objective CR +: Durability ongoing Slovin, et al, ASCO 2009

  22. Conclusions • Safety of Ipilimumab 10 mg/kg +/- additional XRT in patients with mCRPC • No new emergent toxicity due to XRT in 32 subjects • Tolerated in both chemo naïve and chemo experienced population • 15/50 patients (30%) with Grade 3 or 4 irAE • Severity, rate and duration similar to Ipilimumab oncology program • Resolution using established management algorithms • Ten subjects had confirmed 50% reductions in PSA responses (20%) • 2 of these declines were correlated with a serious irAE • Duration of declines: median 30.5 weeks; range: 6.0 to 60+ weeks • Occurrence of declines seen with or without XRT • Occurrence of declines in both chemo naïve and chemo experienced patients • Differences not significant in these small cohorts • Objective response by RECIST) was observed. • All with 50% PSA declines had SD according to RECIST criteria except one patient who had CR for both PSA and RECIST. • Ipilimumab has anti-tumor activity in mCRPC, with and without XRT, and in both the chemo experienced and chemo naïve settings and should be explored in larger studies

  23. Sipuleucel-T Immunotherapy for Advanced Prostate Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial IMPACT STUDY AUA, 2009

  24. Leukapheresis PAP-GM-CSF “Antigen” Isolation of APC Patient Antigen-loaded APCs Vaccination With Antigen (GM-CSF/PAP) Loaded APCs Sheikh et al, 2008.

  25. Small, et al, JCO, 2006

  26. Randomized Phase 3 IMPACT Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment) P R O G R E S S I O N S U R V I V A L Treated at Physician discretion Sipuleucel-T Q 2 weeks x 3 Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) 2:1 Treated at Physician discretion and/or Salvage Protocol Placebo Q 2 weeks x 3 Primary endpoint: Overall Survival Secondary endpoint: Time to Objective Disease Progression

  27. Patient Demographics and Baseline Characteristics

  28. IMPACT Overall Survival: Primary EndpointIntent-to-Treat Population Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. Placebo (n = 171) Median Survival: 21.7 Mos. P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos.

  29. Overall Survival Summary

  30. Survival Consistency Between Population Subsets

  31. Serious Adverse Events*Safety Population *Occurring in ≥ 4 patients.

  32. Consistency Across Phase 3 Studies • *Unadjusted Cox model & log rank • **Cox model adjusted for PSA and LDH

  33. Phase III Study of Sipuleucel-T (D9902B, IMPACT) Adverse Events Post-Study Interventions Kantoff P, et al. 2010 Genitourinary Cancers Symposium. Abstract 8.

  34. Conclusions • Greater awareness of need to standardize immune monitoring for all trials • Improving trial design to address both clinical and research questions – meet expectations of FDA • How to reconcile trials where there is an overall survival benefit in the absence of anti-tumor effect? • Provenge, Prostvac – no impact on PSA or disease? Thoughts?.......

  35. Conclusions • Immunologic tolerance can be broken via multiple vaccine strategies. • Anti-tumor effects documented with possible survival benefits • Concerns: do vaccines need immune modulators to exert more relevant responses? • Is autoimmunity good in the short but bad in the long run?

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