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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 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). Is there a “best” approach? A Whole cell or shed antigen brief history of cancer vaccines (very) Purified protein Peptide Where does immunotherapy end and vaccines begin? PSMA Expression on LNCaP Cell Vaccines: DNA, alhydrogel, DG, VRP T cell MoAbs J415, J591 - ADCC NH2... Extracellular Intracellular MoAb 7E11 ProstaScint Scan Antibody Drug Conjugate: auristatin maytansinoid Cell membrane Modified from P. Smith-Jones 2004 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 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 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 CTLA-4 Blockade Enhances Tumor-Specific Immune Responses Attenuated or Terminated Proliferation Unrestrained Proliferation IL-2 Tumor APC APC Necrotic Death Vaccines Chemotherapy Irradiation Hormone therapy Anti-angiogenesis TCR Peptide/MHC CD28 CTLA-4 B7-1,2 Leach & Allison Science 1996 M.O.A. of CTLA-4 2 1 TCR + Ag on DC = Engagement Door to CTLA-4 activation is closed 3 4 5 Abort! “Go or No Go?”– Awaiting T cell activation or shutdown Full go !! T cell proliferation… or… Skin reactions at the GVAX injection sites GVAX IT alone GVAX IT + MDX-010 (0.3 mg/kg) GVAX IT + MDX-010 (3 mg/kg) After 1 week Injection site reactions were the most common adverse event (100%) No DLTs nor auto-immunity observed PSA curves – Dose Level 3 (3 mg/kg) Pt 7 100 90 80 70 60 50 40 30 20 10 0 60 Pt 8 50 40 a 30 b 20 10 a : 13Mar06: SAE -Hypophysitis (7 mo) b: 03Feb06: Hypophysitis (5 mo) c: 09Feb06: SAE – Hypophysitis (5 mo) Gerritsen, ASCO 2006 3/20/06 2/20/06 1/20/06 12/20/05 11/20/05 10/20/05 9/20/05 8/20/05 7/20/05 6/20/05 4/9/06 3/9/06 2/9/06 1/9/06 12/9/05 11/9/05 10/9/05 9/9/05 c 8/9/05 7/9/05 Pt 9 3/7/06 2/7/06 1/7/06 12/7/05 11/7/05 10/7/05 9/7/05 8/7/05 7/7/05 50 45 40 35 30 25 20 15 10 5 0 6/9/05 6/7/05 0 Patient 8 Bone Scan Improvement in Patient 8 (3 mg/kg) 15Sept05 Gerritsen ASCO2006 29Mar06 Objective Tumor Response Patient 12 (5 mg/kg) 14Feb06 16May06 Gerritsen, ASCO 2006 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 Patient Primary Event Onset Secondary Events 007 Hypophysitis 7 mo Adrenal Insuff 008 Hypophysitis 5 mo Adrenal Insuff 009 Hypophysitis 5 mo Adrenal Insuff Leukopenia Hypothyroidism 010 Hypophysitis 4.5 mo Adrenal Insuff Hypothyroidism 012 Alveolitis (IBE?) 2 mo Low TSH Pathology of Autoimmune Breakthrough Events: Colitis D C E CD4 F CD3 CD8 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). Source: Abstract #3424, ASCO 2003 Rationale: Radiotherapy as an Immune-Supportive Intervention for CTLA-4 Blockade AntiCTLA4 mAb CTLA4 Anti-CTLA4 mAb CTLA-4 Modified after: Demaria, et al, Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 3, pp. 655–666, 2005 Subject 3020, 10 mg/kg monotherapy 200 %Baseline PSA 150 #3020 10 mg/kg mono < 1 cycle (2.5) PSA0= 655 (-) Prior Chemo PSA - CR RECIST - uCR S-irAEs:hepatitis, colitis, irAE - abnormal TFTs 100 50 Hepatitis Colitis abnl TSH PR PR CR PR 0 -4 0 4 8 12 16 20 24 28 Weeks Beer, et al, ASCO 2008 32 36 40 44 48 52 56 60 Subject 3020: Resolution of Prostate Mass Screening 14 months Best PSA Changes: Each Subject Best PSA Change from Baseline (%) 100.00 50.00 0.00 -50.00 -100.00 Mono Slovin, et al, ASCO 2009) XRT in NoCHEMO XRT in CHEMO Time-to-Response and Durability of Confirmed PSA Response *XRT NoCHEMO + *XRT NoCHEMO + XRT NoCHEMO XRT NoCHEMO XRT CHEMO Mono + Mono Mono **Mono + Mono + 0 10 20 30 40 50 60 Weeks Time-to-Response (>50% decrease) *: PSA CR **: Objective CR Response Durability +: Durability ongoing Slovin, et al, ASCO 2009 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 Sipuleucel-T Immunotherapy for Advanced Prostate Cancer: A Randomized, Double-Blind, PlaceboControlled Phase 3 Trial IMPACT STUDY AUA, 2009 Vaccination With Antigen (GM-CSF/PAP) Loaded APCs Leukapheresis PAP-GM-CSF “Antigen” Isolation of APC Patient Sheikh et al, 2008. Antigen-loaded APCs Small, et al, JCO, 2006 Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment) Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) Primary endpoint: Secondary endpoint: Sipuleucel-T Q 2 weeks x 3 2:1 Placebo Q 2 weeks x 3 P R OG R E S S I O N Treated at Physician discretion Treated at Physician discretion and/or Salvage Protocol Overall Survival Time to Objective Disease Progression S U R V I V A L Patient Demographics and Baseline Characteristics Age, median yrs (range) Race, white (%) ECOG status, 0 (%) Gleason Score ≤ 7 (%) Sipuleucel-T (N = 341) 72 (49 – 91) 89.4 82.1 75.4 Placebo (N = 171) 70 (40 – 89) 91.2 81.3 75.4 Disease localization Bone only (%) Soft tissue only (%) Bone & soft tissue (%) >10 bone mets (%) 50.7 7.0 41.9 42.8 43.3 8.2 48.5 42.7 Bisphosphonate use Prior docetaxel (%) 48.1 15.5 48.0 12.3 IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population 100 Percent Survival P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] 75 Median Survival Benefit = 4.1 Mos. 50 Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. 25 Placebo (n = 171) Median Survival: 21.7 Mos. 0 0 6 12 18 24 30 36 42 48 Survival (Months) 54 60 66 Overall Survival Summary Survival Percentiles (months) N 75% 50% 25% Sipuleucel-T 341 15.1 25.8 41.3 Placebo 171 11.0 21.7 35.6 Sipuleucel-T Placebo % Survival (K-M estimates) 24 Mos. 36 Mos. 48 Mos. 52.1 31.7 20.5 41.2 23.0 16.0 Survival Consistency Between Population Subsets Favors sipuleucel-T Bisphosphonate Use: Yes No Primary Gleason Grade: 4 3 No. Bone Metastases: > 10 10 Disease Localization: Single Bone + Soft Tissue ECOG Performance Status: 1 0 Age: Above Median Below Median PSA: Above Median Below Median LDH: Above Median Below Median Alkaline Phos: Above Median Below Median Hemoglobin: Above Median Below Median 0.0 0.5 1.0 1.5 Hazard Ratio (95% Confidence Interval) Serious Adverse Events* Safety Population SAE Preferred Term Any SAE Pyrexia Cerebrovascular accident Pulmonary embolism Spinal cord compression Nausea Atrial fibrillation Dehydration Cardiac failure congestive Pneumonia Hematuria Deep vein thrombosis Renal failure acute *Occurring in ≥ 4 patients. Sipuleucel-T N=338 % 24.0 1.8 1.8 1.2 1.2 0.9 0.9 0.9 0.6 0.6 0.6 0.3 0.3 Placebo N=168 % 23.8 0.6 1.8 0.0 1.2 1.2 0.6 0.6 1.2 1.2 1.2 1.8 2.4 Consistency Across Phase 3 Studies D9901* D9902A* IMPACT ** Integrated** (N = 127) (N = 98) (N = 512) 0.586 0.786 0.775 (N=737) 0.735 p = 0.010 p = 0.331 p = 0.032 p < 0.001 4.5 3.3 4.1 3.9 sipuleucel-T 34% 32% 32% 33% placebo 11% 21% 23% 20% Hazard Ratio p-value Median Survival Benefit (months) 36-Month survival (%) *Unadjusted Cox model & log rank **Cox model adjusted for PSA and LDH Phase III Study of Sipuleucel-T (D9902B, IMPACT) Adverse Events Sipuleucel-T Placebo (n = 341) (n = 171) Chills 54.1% 12.5% Pyrexia 29.3% 13.7% Headache 16.0% 4.8% Myalgia 9.8% 4.8% Post-Study Interventions Sipuleucel-T Placebo (n = 341) (n = 171) Any Intervention 81.8% 73.1% Any Chemotherapy 65.4% 53.8% Docetaxel 57.2% 50.3% Hormone Therapy 12.3% 8.8% Radiation Therapy 21.1% 26.3% Surgical Intervention 1.5% 2.3% Kantoff P, et al. 2010 Genitourinary Cancers Symposium. Abstract 8. 36 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?....... 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?