1 / 38

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.

zody
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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?

More Related