Challenges in Establishing the Role of Immunotherapy in Prostate ...

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Challenges in Establishing the Role of Immunotherapy in Prostate ...

Challenges in Establishing the Role ofImmunotherapy in Prostate CancerSusan F. Slovin, MD, PhDAssociate Attending Physician and Associate MemberMemorial Sloan-Kettering Cancer CenterAssociate Professor of MedicineWeill-Cornell HospitalNew York, New York


Aims• Review approaches to induce anti-tumorresponses by the host• Issues faced in the development of thesestrategies• How to proceed toward successful “drug”development• Goals of the academic / governmental /industrial community2


Pathway to MetastasisPrimary GrowthAngiogenesisDifferentiatingagentsInvasionDetachmentEmbolizationCirculationArrestCarducci MA, et al. Seminars in Oncology. 1996;23:56-62.Local gene therapy (proof of principle)Anti-angiogenesisAnti-metastaticAdhesionCytostatic/Cytotoxic/Pro-apoptoticMMPIVaccine andimmunologic RxExtravasationGrowthMetastasis3


Applicability of Immunotherapyby Clinical StatesPROCastrate, Rising PSAs• Knownnaturalhistory• Time to PODbased on risk• Possibility ofincreasesCTCsCON• Volume ofCTCs• Tumor Ags,unknownPROCastrate Metastatic• Shorter naturalhistory• Larger tumorburden• Expected clinicaloutcome• Increased CTCs• Increased solubletumor Ags• Combination withchemotherapy• Survival preferredFDA endpointCON• Heterogeneouspopulation• No definedimmuneendpoint• Delayedtreatment effect• Intercurrentsymptoms maydelayassessment orlead to ∆ intreatment4


Applicability of Immunotherapyby Clinical StatesPROLocalized: Neoadjuvant• Direct tissueassessment:penetration?• Impact onlocal milieu• Signalingpathways• Easy toscreen novelagents• Likely hittinga targetCON• Systemic• No definedendpoint• Unclear ifany impacton futurePOD• Unclear iftarget is hitPROBiochemically Relapsed• Minimal tumorburdenhistory• Measurementof soluble Ag• High-riskpopulationexistsCON• Long natural• No feasibleendpoint• CTCs minimal• Unclear iftarget is hit5


Issues / Solutions• Harmonization of assays– Established validated assays in designated labs• What are the right assays?– Dependent on the therapy• Reconciliation of assays reflecting impact onbiology of tumor– Impact not always evaluable based on assay6


Unresolved …• Integrate immunotherapy into clinical trial arena: mostproductive clinical state?• If proven efficacy, can one really improve on other endpointsthat are meaningful for the pt, ie QOL, pain, anti-tumor effect,TTP – will it be worth the effort to further develop thestrategy?• Standardize a therapy so that one size fits all, ie, dose, cellnumber, feasibility to general population• +/- chemotherapy? Reasonable without significant data todemonstrate impact on immune cell populations; differentthan that of using cytokines, ie, GM-CSF• Are we leaning toward customized immunotherapy?7


Is There A “Best” Approach?Immunotherapy:Humoral / CellularCompartmentsMonoclonalAntibodies[Passive]Vaccines[Active]T-cellImmunotherapy[Active]10


Controversies …• Defining the immunologic target …Establishing the most appropriate screening assays thatwill allow a “go/no go” approach – demonstratesthat the target has been recognized.• Discordances between immunologic & clinical responses,ie, generation of Abs / immunoreactive T-cells but NOclinical benefit• Establishing relevance of immune responses with clinicaloutcome? Are the current “standards” below the limitsof detectability of the assays?• Should the actual tumor be further examined for trueimmunologic response?11


Lastly …• Does it make a difference whether theimmunologic target is B- or T-cell directed orare both populations needed for maximalimmunologic signal and anti-tumor effects?• Can chronic “inflammatory” conditions suchas prostatitis vs prostate cancer be mediatedby different immunologic responses?12


Rationale for Vaccines in Prostate Cancer1. Well-characterized glycoprotein and carbohydrate “self”antigens: PSA, PSMA, PSCA, ACP, Globo H, GM2,Lewis y , MUC-1,2, Tn, TF, NY-ESO-1, CD147, and CD442. Multiple ways of breaking immunologic tolerance:[viral vectors – 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 states6. Biomarker to study disease progression13


Antibody Responses to Prostate-AssociatedAntigens in Patients With Prostatitis andProstate Cancer• Using a phage immunoblot approach, we evaluated IgG responses inpatients with prostate cancer (n = 126), patients with chronic prostatitis(n = 45), and men without prostate disease (n = 53)• RESULTS: We found that patients with prostate cancer or prostatitis haveIgG specific for multiple common antigens. A subset of 23 proteins wasidentified to which IgG were detected in 38% of patients with prostatecancer and 33% patients with prostatitis versus 6% of controls (P < 0.001and P = 0.003, respectively). Responses to multiple members were nothigher in patients with advanced disease, suggesting antibody immuneresponses occur early in the natural history of cancer progression• CONCLUSIONS: These findings suggest an association betweeninflammatory conditions of the prostate and prostate cancer, and suggestthat IgG responses to a panel of commonly recognized prostate antigenscould be potentially used in the identification of patients at risk for prostatecancer or as a tool to identify immune responses elicited to prostate tissueMaricque BB, et al. The Prostate. 2011;71(2):134-146.14


Work Before Implementation• Identify the targetmolecule(s)• Natural target –omnipresent?• Size: large / small• Level of inherentimmunogenicity• Best method ofinducing immunity• How to prove thatinduction of immunitytruly HITS the target15


A (very) Brief History ofCancer VaccinesWhole cell orshed antigenPurifiedproteinPeptide16


PSMA Expression on LNCaP CellVaccines: DNA,alhydrogel, DG, VRP -T-cellMoAbsJ415, J591 - ADCCNH 2...ExtracellularIntracellularProstaScintScanMoAb 7E11Antibody DrugConjugates:auristatinmaytansinoidCell membraneModified from Smith-Jones PM. The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2004;48(4):297-304.18


Prostate Vaccine Trials Experience …1) Chemical mimes of known cell surface “self” molecules –immunogenic 2) Carriers and adjuvants enhance immunogenicity; change inconformation can affect immunogenicity3) doses of vaccine ≠ augmentation of immunogenicity, ie, lowerdoses – more immunogenic 4) Specific Abs induced but no way to potentiate T-cell responses 5) Immunologic responses - not immediate; no role for boosters6) s in pre- vs posttreatment PSA slopes – No major clinicalimpact on pts with high-risk disease *No clear cut immunologic endpoints. 19


Results of Clinical Trial Endpoints• Tumor responds - target is hit• Tumor responds - target is missed• Tumor respond -target is hit• Tumor respond -target is missedAll say something about the biology of the tumorand how the therapy should be directed20


Problems• How to ensure target is hit• Are we targeting one antigen but impactingon another?• How to reconcile differences in clinical vsimmunologic response• Establishing endpoints that FDA will accept• Standardization / harmonization of immuneassays [“immune monitoring”]21


Do We Need to Change Our CurrentParadigms in Designing Immune-BasedClinical Trials?Sufficient data now exist that we cangenerate humoral / cellular responses; ourimmune read-outs correlate clinically• Despite immune “responses”, target isnot really “hit”; NO direct correlationbetween development of humoral / cellularimmunity and clinical benefit22


Why Have We NotSucceeded, If …?1) Immunogenicity is confirmed, ie, induction ofspecific effector populations, Treg, DC2) Can modulate immune system with cytokinesor checkpoint inhibitors3) Vaccine is safe4) Impact in PSA doubling time or slope5) “Stable disease”6) But … clinical benefit uncertain23


Constructing A BetterVaccine …• Structural conformation• Type of adjuvant• Optimizing systemic conditions:immunosuppressant drugs (CTX); cytokines;immunomodulatory drugs, XRT• Timing may be everything in combinationtherapies and in booster vaccines• Are the issues in clinical trial design or in thetherapy itself?24


Are Single Antigen VaccinesEnough or Are MultipleAntigens Better?25


Flow Cytometric Analyses of Patients’Sera Against MCF-7 Cell LineSlovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930.26


Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930.27


Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930.28


“Treat” by Example• Provenge - Issues of “n” and endpoints+ survival benefit but NOsignificant anti-tumor effectsor ↓ PSA• G-VAX - Chemo combo / trials neg(poor design?)• Tri-Com - Ph II trial survival benefit +Immune response weak but +• Onyvax-P - Data premature• Polyvalent - More ≠ better29


“Treat” by Example• DNA vaccines (PSMA, PSA) –theoretically better, no need for adjuvantdue to CpG repeats but HLA A2+ likelybeneficial• Peptide / CHO vaccines – modest Abresponses, no impact on tumor biology• Checkpoint inhibitors – may be diseasespecificwith robust immune and clinicalresponses (PD-1, renal, melanoma; CTLA-4, melanoma, ovarian, prostate)30


How Can We Maximize An OtherwiseWeak or Poorly Measurable ImmuneResponse?• Cytokines• Release of check-point inhibitors• Inhibitors of immunologic “brakes” within thesystem or “give it the gas” types ofstrategies• Consider pretreatmentimmunosuppressives, ie, cyclophosphamide31


Changing Paradigms• Adoptive immunotherapy +/- cytokines … maybe• Single agent vaccines: enough or just sufficient?... no• Combinatorial approaches:Irradiated tumor cells (antigen integrity]) +/-cytokine(s)/immunomodulatory molecules (B7.1)maybe- Synthetic proteins / peptide / DNA +/- adjuvants- Check-point inhibitors +/- vaccines … likely- Prime boost likely- Vaccine + chemotx / xrtFinding the “right” endpoint that the FDA will accept – will it always besurvival?32


Are Autoimmune Events A Must?• Characteristic of treatment with anti-CTLA-4• Spectrum of effects• Associated with anti-tumor and biomarkereffects• May be variable based on the malignancy• Do the benefits of treatment outweigh thepotential ferocity of some autoimmuneevents?33


6/9/056/7/057/9/057/7/058/9/058/7/059/9/059/7/0510/9/0510/7/0511/9/0511/7/0512/9/0512/7/051/9/061/7/062/9/062/7/063/9/063/7/064/9/066/20/057/20/058/20/059/20/0510/20/0511/20/0512/20/051/20/062/20/063/20/06PSA Curves – Dose Level 3 (3 mg/kg)100908070605040302010060Pt 7 50Pt 8a403020100b50454035302520151050Pt 9ca :b:c:13Mar06: SAE – Hypophysitis(7 mo)03Feb06: Hypophysitis(5 mo)09Feb06: SAE –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, 2006Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.35


Objective Tumor ResponsePatient 12 (5 mg/kg)February 14, 2006 May 16, 2006Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.36


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 hormonereplacement therapyPatient Primary Event Onset Secondary Events007 Hypophysitis 7 months Adrenal insufficiency008 Hypophysitis 5 months Adrenal insufficiency009 Hypophysitis 5 months010 Hypophysitis 4.5 monthsAdrenal insufficiencyLeukopeniaHypothyroidismAdrenal insufficiencyHypothyroidism012 Alveolitis (IBE?) 2 months Low TSHGerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.37


Pathology of AutoimmuneBreakthrough Events: ColitisCDHistopathologic analyses ofselected patients experiencingautoimmune events.EFCD3(C) Colon biopsy from Patient9 illustrating severe colitis withinfiltration of the lamina propriawith neutrophils, lymphocytes,monocytes, plasmacytes, andeosinophils. Neutrophils andlymphocytes also infiltrate thecrypts; numerous mitoticfigures can be seen in theepithelial cells lining the crypts(20X).CD4CD8Immunohistochemistryevaluating expression of CD3+(D), CD4+ (E), and CD8+markers (F) (20X).Phan GQ, et al. Proc Am Soc Clin Oncol. 2003: Abstract 3424.38


Rationale: Radiotherapy As An Immune-Supportive Intervention for CTLA-4 BlockadeAnti-CTLA4mAbCTLA-4Anti-CTLA4mAbCTLA-4Modified from Demaria S, et al. International Journal of Radiation Oncology Biology Physics. 2005;63(3):655-666.39


%Baseline PSASubject 3020, 10 mg/kg Monotherapy20015010050HepatitisColitisabnl TSHPRPR#302010 mg/kg mono< 1 cycle (2.5)PSA 0 = 655(-) Prior ChemoPSA - CRRECIST - uCRS-irAEs:hepatitis, colitis,irAE - abnormal TFTsPRCR0-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60WeeksBeer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S). Abstract 5004.40


Subject 3020:Resolution of Prostate MassScreening14 MonthsBeer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S). Abstract 5004.41


%Baseline PSAResponse Details#3021(CP) @ 10 mg/kg Mono20015010050#302110 mg/kg mono2 cycles (4,2)PSA 0 = 181(-) Prior ChemoSirAE -colitisirAE - hypopitColitisHypopit0-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56Weeks42


Conclusions• Greater awareness of need to standardizeimmune monitoring for all trials• Improving trial design to address bothclinical and research questions – meetexpectations of FDA• Standardization of trial endpoints bynature of the therapy• Combinatorial strategies more appealingbut immune assays must be target-specific43

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