Challenges in Establishing the Role of Immunotherapy in Prostate Cancer Susan F. Slovin, MD, PhD Associate Attending Physician and Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor of Medicine Weill-Cornell Hospital New York, New York Aims вЂў Review approaches to induce anti-tumor responses by the host вЂў Issues faced in the development of these strategies вЂў How to proceed toward successful вЂњdrugвЂќ development вЂў Goals of the academic / governmental / industrial community 2 Pathway to Metastasis Primary Growth Local gene therapy (proof of principle) Anti-angiogenesis Angiogenesis Anti-metastatic Invasion MMPI Detachment Embolization Vaccine and Circulation immunologic Rx Arrest Adhesion Differentiating Extravasation agents Growth Cytostatic/Cytotoxic/Pro-apoptotic Metastasis Carducci MA, et al. Seminars in Oncology. 1996;23:56-62. 3 Applicability of Immunotherapy by Clinical States Castrate, Rising PSAs PRO CON вЂў Known natural history вЂў Time to POD based on risk вЂў Possibility of increases CTCs вЂў Volume of CTCs вЂў Tumor Ags, unknown Castrate Metastatic PRO CON вЂў вЂў вЂў вЂў вЂў вЂў вЂў Shorter natural history Larger tumor burden Expected clinical outcome Increased CTCs Increased soluble tumor Ags Combination with chemotherapy Survival preferred FDA endpoint вЂў вЂў вЂў вЂў Heterogeneous population No defined immune endpoint Delayed treatment effect Intercurrent symptoms may delay assessment or lead to в€† in treatment 4 Applicability of Immunotherapy by Clinical States Localized: Neoadjuvant PRO CON вЂў Direct tissue assessment: penetration? вЂў Impact on local milieu вЂў Signaling pathways вЂў Easy to screen novel agents вЂў Likely hitting a target вЂў Systemic вЂў No defined endpoint вЂў Unclear if any impact on future POD вЂў Unclear if target is hit Biochemically Relapsed PRO CON вЂў Minimal tumor burden history вЂў Measurement of soluble Ag вЂў High-risk population exists вЂў Long natural вЂў No feasible endpoint вЂў CTCs minimal вЂў Unclear if target is hit 5 Issues / Solutions вЂў Harmonization of assays вЂ“ Established validated assays in designated labs вЂў What are the right assays? вЂ“ Dependent on the therapy вЂў Reconciliation of assays reflecting impact on biology of tumor вЂ“ Impact not always evaluable based on assay 6 Unresolved вЂ¦ вЂў Integrate immunotherapy into clinical trial arena: most productive clinical state? вЂў If proven efficacy, can one really improve on other endpoints that are meaningful for the pt, ie QOL, pain, anti-tumor effect, TTP вЂ“ will it be worth the effort to further develop the strategy? вЂў Standardize a therapy so that one size fits all, ie, dose, cell number, feasibility to general population вЂў +/- chemotherapy? Reasonable without significant data to demonstrate impact on immune cell populations; different than that of using cytokines, ie, GM-CSF вЂў Are we leaning toward customized immunotherapy? 7 8 9 Is There A вЂњBestвЂќ Approach? Immunotherapy: Humoral / Cellular Compartments Monoclonal Antibodies [Passive] Vaccines [Active] T-cell Immunotherapy [Active] 10 Controversies вЂ¦ вЂў Defining the immunologic target вЂ¦ Establishing the most appropriate screening assays that will allow a вЂњgo/no goвЂќ approach вЂ“ demonstrates that the target has been recognized. вЂў Discordances between immunologic & clinical responses, ie, generation of Abs / immunoreactive T-cells but NO clinical benefit вЂў Establishing relevance of immune responses with clinical outcome? Are the current вЂњstandardsвЂќ below the limits of detectability of the assays? вЂў Should the actual tumor be further examined for true immunologic response? 11 Lastly вЂ¦ вЂў Does it make a difference whether the immunologic target is B- or T-cell directed or are both populations needed for maximal immunologic signal and anti-tumor effects? вЂў Can chronic вЂњinflammatoryвЂќ conditions such as prostatitis vs prostate cancer be mediated by different immunologic responses? 12 Rationale for Vaccines in Prostate Cancer 1. Well-characterized glycoprotein and carbohydrate вЂњselfвЂќ antigens: PSA, PSMA, PSCA, ACP, Globo H, GM2, Lewisy, MUC-1,2, Tn, TF, NY-ESO-1, CD147, and CD44 2. Multiple ways of breaking immunologic tolerance: [viral vectors вЂ“ fowlpox, VEE, adeno +/- prime boost] 3. Modulation of immune response via cytokines (GM-CSF, IL-2) and immunomodulatory molecules (CD40, PD-1, CTLA-4) 4. Ease of administration [skin] 5. Can be used in all disease states 6. Biomarker to study disease progression 13 Antibody Responses to Prostate-Associated Antigens in Patients With Prostatitis and Prostate Cancer вЂў Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (nвЂ‰=вЂ‰126), patients with chronic prostatitis (nвЂ‰=вЂ‰45), and men without prostate disease (nвЂ‰=вЂ‰53) вЂў RESULTS: We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (PвЂ‰<вЂ‰0.001 and PвЂ‰=вЂ‰0.003, respectively). Responses to multiple members were not higher in patients with advanced disease, suggesting antibody immune responses occur early in the natural history of cancer progression вЂў CONCLUSIONS: These findings suggest an association between inflammatory conditions of the prostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue Maricque BB, et al. The Prostate. 2011;71(2):134-146. 14 Work Before Implementation вЂў Identify the target molecule(s) вЂў Natural target вЂ“ omnipresent? вЂў Size: large / small вЂў Level of inherent immunogenicity вЂў Best method of inducing immunity вЂў How to prove that induction of immunity truly HITS the target 15 A (very) Brief History of Cancer Vaccines Whole cell or shed antigen Purified protein Peptide 16 17 PSMA Expression on LNCaP Cell Vaccines: DNA, alhydrogel, DG, VRP T-cell NH2... MoAbs J415, J591 - ADCC Extracellular Intracellular MoAb 7E11 ProstaScintпѓ¤ Scan Antibody Drug Conjugates: auristatin maytansinoid Cell membrane Modified from Smith-Jones PM. The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2004;48(4):297-304. 18 Prostate Vaccine Trials Experience вЂ¦ 1) Chemical mimes of known cell surface вЂњselfвЂќ molecules вЂ“ immunogenic пѓ– 2) Carriers and adjuvants enhance immunogenicity; change in conformation can affect immunogenicity 3) п‚ doses of vaccine в‰ augmentation of immunogenicity, ie, lower doses вЂ“ more immunogenic пѓ– 4) Specific Abs induced but no way to potentiate T-cell responses пѓ– 5) Immunologic responses - not immediate; no role for boosters 6) пЃ„s in pre- vs posttreatment PSA slopes вЂ“ No major clinical impact on pts with high-risk disease пѓ– пѓ– *No clear cut immunologic endpoints.пѓ– пѓ– пѓ– 19 Results of Clinical Trial Endpoints вЂў Tumor responds - target is hit вЂў Tumor responds - target is missed вЂў Tumor п‚№ respond - target is hit вЂў Tumor п‚№ respond - target is missed All say something about the biology of the tumor and how the therapy should be directed 20 Problems вЂў How to ensure target is hit вЂў Are we targeting one antigen but impacting on another? вЂў How to reconcile differences in clinical vs immunologic response вЂў Establishing endpoints that FDA will accept вЂў Standardization / harmonization of immune assays [вЂњimmune monitoringвЂќ] 21 Do We Need to Change Our Current Paradigms in Designing Immune-Based Clinical Trials? Sufficient data now exist that we can generate humoral / cellular responses; our immune read-outs correlate clinically вЂў Despite immune вЂњresponsesвЂќ, target is not really вЂњhitвЂќ; NO direct correlation between development of humoral / cellular immunity and clinical benefit 22 Why Have We Not Succeeded, If вЂ¦? 1) Immunogenicity is confirmed, ie, induction of specific effector populations, Treg, DC 2) Can modulate immune system with cytokines or checkpoint inhibitors 3) Vaccine is safe 4) Impact in PSA doubling time or slope 5) вЂњStable diseaseвЂќ 6) But вЂ¦ clinical benefit uncertain 23 Constructing A Better Vaccine вЂ¦ вЂў Structural conformation вЂў Type of adjuvant вЂў Optimizing systemic conditions: immunosuppressant drugs (CTX); cytokines; immunomodulatory drugs, XRT вЂў Timing may be everything in combination therapies and in booster vaccines вЂў Are the issues in clinical trial design or in the therapy itself? 24 Are Single Antigen Vaccines Enough or Are Multiple Antigens Better? 25 Flow Cytometric Analyses of PatientsвЂ™ Sera Against MCF-7 Cell Line Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930. 26 27 Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930. 28 Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930. вЂњTreatвЂќ by Example вЂў Provenge - вЂў G-VAX - вЂў Tri-Com - вЂў Onyvax-P вЂў Polyvalent - Issues of вЂњnвЂќ and endpoints + survival benefit but NO significant anti-tumor effects or в†“ PSA Chemo combo / trials neg (poor design?) Ph II trial survival benefit + Immune response weak but + Data premature More в‰ better 29 вЂњTreatвЂќ by Example вЂў DNA vaccines (PSMA, PSA) вЂ“ theoretically better, no need for adjuvant due to CpG repeats but HLA A2+ likely beneficial вЂў Peptide / CHO vaccines вЂ“ modest Ab responses, no impact on tumor biology вЂў Checkpoint inhibitors вЂ“ may be diseasespecific with robust immune and clinical responses (PD-1, renal, melanoma; CTLA4, melanoma, ovarian, prostate) 30 How Can We Maximize An Otherwise Weak or Poorly Measurable Immune Response? вЂў Cytokines вЂў Release of check-point inhibitors вЂў Inhibitors of immunologic вЂњbrakesвЂќ within the system or вЂњgive it the gasвЂќ types of strategies вЂў Consider pretreatment immunosuppressives, ie, cyclophosphamide 31 Changing Paradigms вЂў Adoptive immunotherapy +/- cytokines вЂ¦ maybe вЂў Single agent vaccines: enough or just sufficient?... no вЂў Combinatorial approaches: Irradiated tumor cells (antigen integrity]) +/cytokine(s)/immunomodulatory molecules (B7.1) maybe - Synthetic proteins / peptide / DNA +/- adjuvants - Check-point inhibitors +/- vaccines вЂ¦ likely - Prime boost likely - Vaccine + chemotx / xrt Finding the вЂњrightвЂќ endpoint that the FDA will accept вЂ“ will it always be survival? 32 Are Autoimmune Events A Must? вЂў Characteristic of treatment with anti-CTLA-4 вЂў Spectrum of effects вЂў Associated with anti-tumor and biomarker effects вЂў May be variable based on the malignancy вЂў Do the benefits of treatment outweigh the potential ferocity of some autoimmune events? 33 PSA Curves вЂ“ Dose Level 3 (3 mg/kg) 100 90 80 70 60 50 40 30 20 10 0 60 Pt 7 Pt 8 50 40 a 30 b 20 10 4/9/06 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 3/7/06 3/9/06 1/9/06 12/9/05 11/9/05 10/9/05 9/9/05 8/9/05 7/9/05 6/9/05 2/7/06 1/7/06 12/7/05 11/7/05 10/7/05 9/7/05 8/7/05 c Pt 9 2/9/06 50 45 40 35 30 25 20 15 10 5 0 7/7/05 6/7/05 0 a : 13Mar06: SAE вЂ“ Hypophysitis (7 mo) b: 03Feb06: Hypophysitis (5 mo) c: 09Feb06: SAE вЂ“ Hypophysitis (5 mo) Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500. 34 Bone Scan Improvement in Patient 8 (3 mg/kg) September 15, 2005 March 29, 2006 Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500. 35 Objective Tumor Response Patient 12 (5 mg/kg) February 14, 2006 May 16, 2006 Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500. 36 Immune Breakthrough Events (IBE) вЂў No IBE in DL 1 and 2 вЂў 5 of 6 patients in 3 mg/kg and 5 mg/kg with IBE вЂ“ All associated with PSA response вЂ“ All delayed вЂ“ All endocrine-related & treatable with standard hormone replacement therapy Patient Primary Event Onset Secondary Events 007 Hypophysitis 7 months Adrenal insufficiency 008 Hypophysitis 5 months Adrenal insufficiency 009 Hypophysitis 5 months Adrenal insufficiency Leukopenia Hypothyroidism 010 Hypophysitis 4.5 months Adrenal insufficiency Hypothyroidism 012 Alveolitis (IBE?) 2 months Low TSH Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500. 37 Pathology of Autoimmune Breakthrough Events: Colitis D C Histopathologic analyses of selected patients experiencing autoimmune events. CD3 E F CD4 Phan GQ, et al. Proc Am Soc Clin Oncol. 2003: Abstract 3424. CD8 (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). 38 Rationale: Radiotherapy As An ImmuneSupportive Intervention for CTLA-4 Blockade AntiCTLA4 mAb CTLA-4 Anti-CTLA4 mAb CTLA-4 Modified from Demaria S, et al. International Journal of Radiation Oncology Biology Physics. 2005;63(3):655-666. 39 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 32 36 40 44 48 52 56 60 Weeks Beer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S). Abstract 5004. 40 Subject 3020: Resolution of Prostate Mass Screening 14 Months Beer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S). Abstract 5004. 41 Response Details #3021(CP) @ 10 mg/kg Mono 200 %Baseline PSA 150 #3021 10 mg/kg mono 2 cycles (4,2) PSA0 = 181 (-) Prior Chemo SirAE -colitis irAE - hypopit 100 50 Colitis Hypopit 0 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Weeks 42 Conclusions вЂў Greater awareness of need to standardize immune monitoring for all trials вЂў Improving trial design to address both clinical and research questions вЂ“ meet expectations of FDA вЂў Standardization of trial endpoints by nature of the therapy вЂў Combinatorial strategies more appealing but immune assays must be target-specific 43