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Immuno-Oncology: A Colloquium on the State of the Science for Oncology Clinicians


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More information about this activity can be found here:

Jedd D. Wolchok, MD, PhD
Memorial Sloan-Kettering Cancer Center

Antoni Ribas, MD, PhD
University of California, Los Angeles

Mary L. Disis, MD
University of Washington School of Medicine

Charles G. Drake, MD, PhD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

John Powderly II, MD, CPI
Carolina BioOncology Institute, PLLC
Cancer Therapy & Research Center

Activity Overview

Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumors, generating renewed interest in novel immunologic approaches to the treatment of cancer. Indeed, there have been multiple FDA approvals of immunologic agents in recent years and there are many ongoing trials of novel immunotherapies in lung cancer, colorectal cancer, and other tumor types.

In this series of half-day conferences, leading oncologists will provide an overview of immune system–cancer interactions, the safety and efficacy of recently approved immunologic agents for the treatment of melanoma and prostate cancer, the latest data from ongoing trials in non-small cell lung cancer, colorectal cancer, and others, and the management of immune-related adverse events (IRAEs). These sessions will include case studies to stimulate interactive discussion of real-world treatment scenarios.

Learning Objectives
Upon completion of this activity, participants should be better able to:

• Describe the biological foundations of immunotherapy approaches to the
treatment of cancer
• Identify the mechanisms of action of immuno-oncologic agents such as
vaccines and immune system-modulating antibodies
• Evaluate new safety and efficacy data on recently approved and emerging
immunotherapies across tumor types
• Describe how new immunotherapies are integrated into existing treatment
evidence-based guidelines
• Identify ongoing research efforts in immuno-oncology including how to
appropriately select patients who would be candidates for clinical trials

More information about this activity can be found here:

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Immuno-Oncology: A Colloquium on the State of the Science for Oncology Clinicians

  1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on for details.
  2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
  3. 3. Disclosure of Conflicts of InterestJedd D. Wolchok, MD, PhD, reported a financial interest/relationship or affiliationin the form of: Consultant, Bristol-Myers Squibb Company.Mary (Nora) L. Disis, MD, reported a financial interest/relationship or affiliation inthe form of: Consultant, Bristol-Myers Squibb Company, EMD Serono, Inc.,Immunovaccine, Inc., Hoffmann-La Roche, Inc., VentiRX Pharmaceuticals;Contracted Research, GlaxoSmithKline plc.; Ownership Interest, Epigenomics AG.Charles G. Drake, MD, PhD, reported a financial interest/relationship or affiliationin the form of: Royalty, Amplimmune, Inc., Bristol-Myers Squibb Company; Receiptof Intellectual Property Rights/Patent Holder, Amplimmune, Inc., Bristol-MyersSquibb Company; Consultant, Bristol-Myers Squibb Company, DendreonCorporation, Pfizer, Inc.; Ownership Interest, Amplimmune, Inc.John Powderly II, MD, CPI, reported a financial interest/relationship or affiliation inthe form of: Receipt of Intellectual Property Rights/Patent Holder, BioCytics®;Consultant, Amplimmune, Inc., Bristol-Myers Squibb Company; Speakers Bureau,Bristol-Myers Squibb Company; Contracted Research, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech, Inc.; Ownership Interest, BioCytics®.
  4. 4. 5 Disclosure of Conflicts of InterestAntoni Ribas, MD, PhD, reported a financial interest/relationship or affiliation in theform of: Consultant, Amgen, Inc., Celgene Corporation, Genentech- A member ofthe Roche Group, GlaxoSmithKline plc., Millennium Pharmaceuticals, Inc.,Prometheus.Scott N. Gettinger, MD, has no real or apparent conflicts of interest to report.Mario Sznol, MD, reported a financial interest/relationship or affiliation in the formof: Consultant, Anacor Pharmaceuticals, Inc., BeiGene LTD, Bristol-Myers SquibbCompany, Genesis Biopharma, Necktar Pharmaceuticals Inc., Prometheus;Ownership Interest, Genesis Biopharma.
  5. 5. Welcome and Introduction Jedd D. Wolchok, MD, PhDMemorial Sloan-Kettering Cancer Center
  6. 6. Immuno-Oncology: The Biological Foundations Mary L. Disis, MDUniversity of Washington School of Medicine
  7. 7. Immuno-Oncology: The Biological Foundations The immune system Cancer and the immune system The basics of immune therapy
  8. 8. The Immune System T cell (orange) killing a cancer cell (magenta) CHARACTERISTICS INNATE ADAPTIVE Specificity Non-Specific Specific Antigens Not Needed Required Memory None Generated Time Course Immediate Slowly Developing Duration Transient Lifelong Cell Types MØ, DC, NK, T Cells, B Cells Neutrophil First Line of Defense Effectors Immune SensorsMØ = macrophages; DC = dendritic cell; NK = natural killer cell.Alberts et al, 2002; Murphy et al, 2008.
  9. 9. Cells of the Innate Immune System Neutrophil Phagocytosis and debris clean up Secrete chemokines that call in other innate immune cells Dendritic Cell Potent antigen presenting cells (APC) Uptake and process antigen Both “class I” and “class II” pathways Will stimulate both CTL and T helper (Th) cells Macrophage Phagocytosis and cleaning up debris, secrete cytokines Type 1 can turn on adaptive immunity Type 2 will limit adaptive immunity Natural Killer Cell Can directly kill tumor without docking to MHC Secrete high levels of IFN-gamma (critical cytokine) Antibodies can activate them via FC receptor (ADCC)ADCC = antibody-dependent cell-mediated cytotoxicity; MHC = major histocompatibility center; IFN = interferon; CTL = cytotoxic T lymphocytes.Alberts et al, 2002; Murphy et al, 2008.
  10. 10. Cells of the Adaptive Immune System Humoral Immunity Cellular Immunity Extracellular microbes (e.g., bacteria) Intracellular microbes (e.g., viruses) B lymphocytes Processed and B Antigen-presenting B presented antigen cell Helper Secreted T-cell antibody T T-cell receptor Cytokines Cytokine Proliferation and receptor Neutralization activation of effector cells Lysis (complement) (cytotoxic T-cells, Phagocytosis natural killer cells, (PMN, macrophage) macrophages) Lysis of infected cellPMN = polymorphonuclear leukocyt.Kumar, et al 2007.
  11. 11. Critical Link Between Innate and Adaptive Immunity MHC II TCR CD4 CD4+ Activation T-cell Apoptotic cell CD40L CD40 Immature MHC I dendritic cell Necrotic cell • Activation TLR • Proliferation • CTL generation Activation Mature CD8 dendritic cell Immature CD8+ dendritic cell Pathogen T-cellTCR = T cell receptor; TLR = Toll-like receptors.Bevan, 2004.
  12. 12. The Immune System Is All About “Checks and Balances” Tumor Regression Regulatory loops Tumor Progression NK/NKT T H1 TH17 TH17 B cell T H2 TREG DC1 N1 N2 DC2 M1 M2 Myeloid Phenotype Angiostatic Pro- angiogenic Direct Tissue cytotoxicity remodeling Immune Immune surveillance suppression IL-12, IL-2, IFN-g, TNF-a IL-4, IL-5, IL-10, TGF-bIL = Interleukin; TNF = tumor necrosis factor; TGF = transforming growth factor.DeNardo et al, 2010.
  13. 13. Immuno-Oncology: The Biological Foundations The immune system Cancer and the immune system The basics of immune therapy
  14. 14. Steps in Stimulating Cancer Specific Immunity Melanoma “Danger” e.g. HSP IFN-α CD28 MAGE I B7 CD8 MARTI CTL Help (TAAs) APC e.g. CD40 CD40 IL-2 CD4 Immature DC CD40L TH Activated mature DC Lymph node B7 CD40L CD40 CD8 CD28 CD40 CD4 TCR Migration from TCR lymph node MHC I MHC II DC Migration to lymph node
  15. 15. Epitope Spreading Is the Endpoint of an Effective Immune Response in CancerMIP-1α= macrophage inflammatory protein 1α.Vanderlught et al, 2002.
  16. 16. What Is Needed for Clinical Effective Antitumor Immunity? High Density of T Cells Modulation of Type I Inflammation Penetrating Tumor Self-Regulation 0 .1 6 10 105 Murine TNBC 4 10 < F IT C - A > : F O X P 3 3 10 2 10 Murine TNBC 0 43 46 FOXP3 2 3 4 5 0 10 10 10 10 < P e rC P -C y 5 -5 -A > : C D 4 0 .8 8 1 .1 105 4 10 < F IT C -A > : F O X P 3 Murine ER+BC 3 10 2 10 Murine breast tumor Murine ER+ BC 0 after activating the 46 52 2 3 4 5 Immune system 0 10 10 1 0 10 < P e rC P -C y 5 -5 -A > : C D 4  75 colorectal cancers  7 gene classifier  186 advanced ovarian cancers CD4  Inverse correlation of gene  MVA: Intratumoral T cells  237 breast cancers expression and relapse independent predictor survival  MVA: Density of Treg+ in ER+ tumors predictor of survivalMVA = multivariate regression analysis; ER+ = estrogen receptor positive; Treg = regulatory T cells.Galon et al, 2006; Zhang et al, 2003; Bates et al, 2006.
  17. 17. Optimal Immune Reaction Many cancer patients have demonstrated an “optimal immune reaction”VEGF = vascular endothelial growth factor; CT = center; IM = invasive margin.Bindea et al, 2010.
  18. 18. What Does the Immune System See in Cancer? Cell and Cell and Tumor Cell and Self Virus Antigen Protein Only Antigens Associated With Clinical Response Foreign Self Antigens Antigens LMP2 HER2 GD2 HPV WT1 CEA HepB MUC1 MART-1 Dangerous Weak Tolerizing • Cell damage • None of MAGE A2 gp100 • No danger (uric acid) signals these NY-ESO-1 PR1 • Innate • No CD40 signals immunity signals PSMA Tyrosinase activated • Pro- • TLRs PSA PAP inflammatory triggered cytokines PSCA NA17 • Inflammation • Cytokines • CD40 signals • OthersLake et al, 2005; Cheever et al, 2009.
  19. 19. Why Do Most Tumors Evade Immune Recognition?Murphy et al, 2008.
  20. 20. Multiple Factors Impact the Tumor Immune Microenvironment Pro-Tumorigenic Anticancer Inflamation Immunosurveillance Cell Types M2 macrophages Dendritic cells Myeloid-derived suppressor M1 macrophages cells cytotoxic CD8+ T cells with a Neutrophils memory effector phenotype Foxp3+ T reg. Th17 cells Cytokine Th2, Th17 Th1 Profiles CX3CL1 CXCL9, CXCL10 Distribution Peritumoral Intratumoral, close to cancer cells, as well as in the invasive front Associated Stat3 phosphorylation High endothelial venules Features Functional Negative prognostic impact Positive prognostic and Impact predictive impactFoxp3 = forkhead box P3.Fridman et al, 2011; Disis, 2010a.
  21. 21. Immuno-Oncology: The Biological Foundations The immune system Cancer and the immune system The basics of immune therapy
  22. 22. Types of Immune Therapy PASSIVE ACTIVE Transferred Generated Ready Made Must Be Developed Immediate Protection Takes Time No Memory Long Lived Immune System May Requires Functional Immune Function Poorly System Ig Infusions, Some MoAB Vaccines, Anti-CTLA-4 Therapy, T-Cell TransferIg = immunoglobulins; MoAB = monoclonal antibody; CTLA-4 = cytotoxic T-lymphocyte antigen-4.Murphy et al, 2008.
  23. 23. Monoclonal Antibody Therapy: TrastuzumabHER-2/neu = human epidermal growth factor receptor 2. Time (Weeks)Ferris et al, 2010; Taylor et al, 2007; Ladoire et al, 2011.
  24. 24. Adoptive T Cell Therapy Factors Associated With Clinical Response Diversity Objective Response  Unfractionated TIL 34%-50% polyclonal  Selected tumor- reactive TIL 49%-72% TCR gene transfer (MART-1/Melan-A, 13%-30% gp100,NY-ESO-1) 50% response rate 20/93 complete responders monoclonal  Individual T cell clones (MART-1/Melan-A, 0%-11% gp100,NY-ESO-1) SpecificityTIL = tumor-infiltrating lymphocytes; CR = complete response; PR = partial response; NR = no response; MART-1/ Melan-A = melanomaantigen recognized by T-cells, gp100 = glycoprotein 100; NY-ESO-1 = immunogenic peptide derived from the cancer-testis antigen.Topalian et al, 2011; Rosenberg et al, 2011.
  25. 25. Immuno-Oncology: The Biological Foundations T1 T2Tx = treatment.Disis, 2010b.
  26. 26. Key Takeaways Innate immunity, our first responders that don’t require antigen recognition, can support and enhance the efficacy of adaptive immunity cells that are specific to an invader Therapeutic immunity can be either passive (supplying an antibody response) or active (vaccinating to create your won antibody response) which requires your immune system to do the work There is strong evidence that most cancers stimulate the immune system Efficacy of cancer-induced immunity is limited by both factors secreted by the tumor and stroma, but also normal defense mechanisms activated to prevent autoimmunity Our improved understanding of tumor-immune system interactions has led to design of therapeutic approaches that both stimulate immunity and address mechanisms of immune escape There are now several promising immunologic agents that have demonstrated significant antitumor efficacy in advanced stage clinical trials or have been approved for standard of care use
  27. 27. Audience Q&A: The Biological Foundations of Immunotherapy Mary L. Disis, MDUniversity of Washington School of Medicine
  28. 28. Immuno-Oncology: Genitourinary Cancers Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  29. 29. Outline  Cancer “Vaccines”  Combination – Sipuleucel-T Immunotherapy – ProstVac VF – With androgen-ablation – Argos AGS-003 – With TKIs  Immune Checkpoint  Integrating immunotherapy Blockade into the current (and future) prostate cancer – Anti-CTLA-4, ipilimumab treatment paradigm – Anti-PD-1, BMS-936558 (MDX-1106) – Phase III trial designPD-1 = programmed cell death protein-1; TKIs = tyrosine kinase inhibitors.
  30. 30. Cancer Vaccines: An Immunological MOA CD4 T Cell Activated TCR Dendritic Cell Class II MHC TCR Cytokines = HELP Tumor Antigen Class I MHC CD8 T Cell Activated CD8 T Cells Traffic to Tumor and Lyse Tumor CellsMOA = mechanism of action.Burch et al, 2000; Small et al 2000; Fong et al, 1997.
  31. 31. Active Cellular Immunotherapy Sipuleucel-T Patient WBC Harvested GM-CSF Short-Term Culture With Protein “Cassette” PAP Shipping Cells Infused BACK Into Patient (IV)WBC = white blood count; GM-CSF = granulocyte-macrophage colony stimulating factor;PAP = prostatic acid phosphatase; IV = intravenous.Burch et al, 2000; Small et al, 2000.
  32. 32. D9902B – IMPACT Immunotherapy Prostate Adenocarcinoma Treatment P R R A Placebo q2wks Eligible for x3 O Sipuleucel-Ta N  mCRPC G D  No Visceral R O Mets E  N = 512 M S I Sipuleucel-T Physician’s S Z q2wks x 3 Discretion I E O N  Patients: Asymptomatic or minimally symptomatic mCRPC  Primary end point: OS  Secondary end point: TTPa Prepared from cryo-preserved lymphocytes.mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; TTP = time to progression.Kantoff et al, 2010a.
  33. 33. IMPACT OS: Primary End Point ITT Population 100 p = .032 (Cox model) HR = 0.775 [95% CI 0.614, 0.979] 75 Percent Survival Median Survival Benefit = 4.1 mos 50 Sipuleucel-T (n = 341) Median Survival = 25.8 mos Placebo (n = 171) 25 Median Survival = 21.7 mos 0 0 6 12 18 24 30 36 42 48 54 60 66ITT = intent-to-treat; HR = hazard ratio; CI = confidence interval.Kantoff et al, 2010a.
  34. 34. Madan et al, 2009; Sonpavde et al, 2011. DNA = deoxyribonucleic acid; PSA = prostate-specific antigen. Co-Stimulatory Molecules PSA B7-1 ICAM-1 LFA-3 Target Antigen Vaccinia Virus Fowlpox Virus Plasmid DNA Packaging Cell Line rV-PSA- TRICOM rF-PSA- TRICOM VaccineA Viral Vaccine Approach: ProstVac VF
  35. 35. Viral Vaccines – Same Idea: But Starting At A Different Step ProstVac VF CD4 T Cell TCR Class II MHC TCR Class I MHCEpithelial Cells CD8 T Cell ACTIVATED Cell Death - Necrosis CD8 T CellMadan et al, 2009; Sonpavde et al, 2011.
  36. 36. TBC-PRO-002 Survival Data Time (mos) Design: Nearly identical to IMPACT but NO crossover Patients: mCRPC with either no or minimal symptoms Primary end point: TTPCRPC = castration-resistant prostate cancer; TTP = time to progression.Kantoff et al, 2010b.
  37. 37. Prospect Trial: Design (SPA) Phase III Global (US-CAN-AUS/WE/EE/Latin America) PROSTVAC-(V)(F) TRICOM + Low-Dose S Adjuvant GM-CSF Non/Minimally U Symptomatic R mCRPC PROSTVAC-(V)(F) V TRICOM Standard Adjuvant Placebo of Care I No Crossover V Vector Placebo A Adjuvant Placebo L Primary End Point: OSSPA = special protocol assessment.US NIH, NCT01322490.
  38. 38. Using RNA to Load Dendritic Cells Argos AGS-003 Kidney Cancer Sample Tumor Load DC With RNA RNA Isolation And Activate (AGS-003) Cryopreserve Leukapheresis DC Product Manufacture Intranodal InjectionRNA = ribonucleic acid.Figlin et al, 2012.
  39. 39. ADAPT: Autologous Dendritic Cell Immunotherapy With AGS-003 Plus Sunitinib for the Treatment of Advanced RCC R AGS-003 A 1 Cycle Sunitinib AGS-003 5 doses q3mos  Metastatic, N (6 wks) q3wks Unfavorable D Risk Clear O Cell RCC M  N = 450 I 1 Cycle Sunitinib Placebo Z (6 wks) q3mos E Ongoing Sunitinib (4 wks on, 2 wks off)  Primary end point: OS  Secondary end point: PFS (30% increase), ORR, safety  FDA approved the SPA for the phase III clinical study of AGS-003 for the treatment of metastatic RCC  Study has initiated and is expected to begin dosing patients in the second half of 2012RCC = renal cell carcinoma; ORR = overall response rate; PFS = progression-free survival.US NIH, NCT01582672.
  40. 40. Normal T-Cell Activation T Cell TCR CD28 Signal 1 Signal 2 antigen HLA B7.1/2 Antigen Presenting CellHLA = human leukocyte antigen.Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
  41. 41. Immune Checkpoints (CTLA-4) Prevent Normal T-Cell Activation T Cell CTLA-4 TCR CD28 Signal 1 Signal 2 antigen HLA B7.1/2 Antigen Presenting CellKirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
  42. 42. Ipilimumab (Anti-CTLA-4) Blocks the CTLA-4 Checkpoint, Restoring T-Cell Activation Antigen Presenting Cell HLA B7.1/2 CTLA-4 antigen Signal 1 Signal 1 Signal 2 Signal 2 TCR CD28 CTLA-4 T CellKirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
  43. 43. CTLA-4 Blockade: (Ipilimumab, Tremelimumab)  Single-agent activity – RR = 15%–20%  Regressions = durable  Regressions = delayed  Grade III/IV SAE = 10%–15% – Colitis – Hypophysitis  PSA Responses in PC (N = 200) – 20%RR = response rate; SAE = serious adverse event; PSA = prostate-specific antigen; PC = prostate cancer.Saenger et al, 2008; courtesy of Jedd D. Wolchok, MD, PhD.
  44. 44. Ipilimumab in Melanoma: The First “Drug” Ever to Show a Survival Benefit in a Randomized Clinical Trial Comparison HR P-value Arm A vs C 0.68 0.0004 Arm B vs C 0.66 0.0026 Arm A vs B 1.04 0.7575 Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) 1 2 3 4 Years Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-yr 44% 46% 25% 2-yr 22% 24% 14%Hodi et al, 2010.
  45. 45. Randomized, Double-Blind, Phase III Trial Comparing Ipilimumab Vs. Placebo Following Radiotherapy in Subjects With CRPC That Have Received Prior Treatment With Docetaxel (CA184-043) SCREENING INDUCTION MAINTENANCE Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg CRPC Wks 1, 4, 7, 10 q12wks Radiotherapy (8 gy) Prior to bone metastases Docetaxel IVRS Day -2 or -1 Placebo Placebo N = 800 Wks 1, 4, 7, 10 q12wks ICF, Baseline TA: Wks 12, 24 TA: q12wks PSA: Wks 7, 12, 18, 24 PSA: q6wks Assessments OA: Wks 7, 10, 12, 18, 24 OA: q12wks Day -28 to -2 Day -2 to Wk 24 Wk 24 to 48+Completed Accrual 1/2012TA = tumor assessment; OA = outcome assessment; ICF = informed consent form; IVRS = interactive voice response system.US NIH, NCT00861614.
  46. 46. Immune Checkpoint Blockade 2: PD-1 Tumor Cell or Antigen Presenting Cell T Cell Signal 2 B7.1/2 CD28 Signal 1 CTLA- 4 HLA antigen TCR Class II LAG-3 MHC B7-H1 PD-1 (PD-L1) Others: ICOS, GITR, Tim-3Weber, 2010; Pardoll, 2012a.
  47. 47. Immune Resistance: PD-1 Innate Immune Resistance MHC + Peptide TCR Tumor T Cell Oncogene-Driven PD-L1 Expression Oncogenic Pathway PD-1 PD-L1 Adaptive Immune Resistance Tumor T Cell Tumor T Cell PD-L1 Adaptive Up-Regulation Interferon g Of PD-L1 Turns T Cell OFFPardoll, 2012a.
  48. 48. First BMS-936558 (MDX-1106) Phase I Trial Follow Up or Additional 1st Treatment Cycle Treatment Cycle(s) Day 1 Day 29 Day 57 Day 85 2 years 60 minute IV Optional tumor bx Or until PD Scans infusion 10mg/kg Optional tumor bx 2 doses 4 wks apart, follow SD or mixed response 12 more weeks, can repeat Follow up every month x 2 PR or CR then every 2 months, Re-treat on progressionSD = stable disease; MR = mixed response; PD = progression disease.Brahmer et al, 2010.
  49. 49. BMS-936558 (MDX-1106) Phase I: Summary Toxicities (39 patients)  Grade 1: Pruritis, rash, fatigue  Grade 2: – Polyarticular arthropathy, 2 patients (3 mg/kg and 10 mg/kg), treated with oral steroids – TSH elevation, 4 patients (1 patient requiring levothyroxine)  Grade 3: Colitis, 1 patient after multiple doses at 1 mg/kg Response – MR (2), PR (2), CR (1)Brahmer et al, 2010.
  50. 50. PD-1 Blockade: Results in Increased CD8 T Cells in Tumors Pre-Rx c m 12-wk Post Dose 1cm 8-wk Post Dose 3 cm 3.9 2.6 2.4 Anti-CD8 Anti-CD8 Anti-CD8 Pre-Rx 4-wk Post Dose 1 4-wk Post Dose 3Rx = treatment.Brahmer et al, 2010.
  51. 51. Durable Responses to Anti-PD-1 OFF THERAPY Pt 2- 2013 CR Stop Rx Latest Evaluation: CR 0 1 yr 2 yr 3 yr 4 yr ? new brain met on MRI Pt 1- Stop Best resected: - no viable tumor 4033 Rx resp.(PR) Latest Evaluation: CR Sustained PR 0 1 yr 2 yr 3 yr 4 yr Pt 1- Stop Best New LN mets Restart a PD-1 3019 Rx resp.(PR) Sustained PR 0 1 yr 2 yr 3 yr 4 yrMRI = magnetic resonance imaging; LN = lymph node.Brahmer et al, 2010.
  52. 52. Multidose Phase Ib Trial of Anti-PD-1 (BMS-936558/MDX 1106)cCR = confirmed complete response; uCR = unconfirmed complete response; uPD = unconfirmed progressive disease;wPD = worsening progressive disease.McDermott et al, 2011.
  53. 53. Efficacy Results: RCC Patients Changes in Target Lesions Over Time in RCC PatientsMcDermott et al, 2012.
  54. 54. Anti-PD-1 (BMS-936558) Dose Finding Study CA209010 Arm 1 n = 50 Prior Anti- BMS-936558 (0.3 mg/kg) IV q3wks Angiogenic Tx Arm 2 n = 50 (1:1:1 Randomization) BMS-936558 (2 mg/kg) IV q3wks N = 150 Arm 3 n = 50 BMS-936558 (10 mg/kg) IV q3wks 1° end point: PFS as measured by TA 2° end points: PFS, ORR, OS Completed Accrual 12/2011US NIH, NCT01354431.
  55. 55. Anti-PD-1 (BMS-936558) Biomarker Study CA209009 Arm 1 n = 20 Prior Anti- BMS-936558 (0.3 mg/kg) IV q3wks Angiogenic Tx (1:1:1 Arm 2 n = 20 Randomization) BMS-936558 (2 mg/kg) IV q3wks N = 80 Arm 3 n = 20 BMS-936558 (10 mg/kg) IV q3wks Treatment Arm 4 n = 20 (treatment naïve arm) Naïve BMS-936558 (10 mg/kg) IV q3wks 1° end point: Measurement of immunomodulatory activity 2° end points: PFS, ORR, safety, and tolerability Treatment Naïve Cohort Closed 2/2012 Other Cohorts OpenUS NIH, NCT01358721.
  56. 56. Why Has Immunotherapy Been Successful in Prostate Cancer?  Better “Vaccines” ? – Sipuleucel-T = Ex-Vivo Culture – ProstVac = Heterologous Prime Boost (+ costimulation)  Better Antigens? – PAP (no tolerance in animals) – PSA (role in tumor progression)  Prostate Cancer = Better Target? – Slow Growing – Patient Selection (asymptomatic or minimally symptomatic) – Patients = CastrateCha et al, 2011; Makarov et al, 2009.
  57. 57. Effect of Androgen-Ablation on T-Cell ResponseDrake et al, 2005.
  58. 58. Testing the Optimal Sequencing of Androgen-Ablation and “Vaccination” P10-2 Study Participation Concludes Eligibility Treatment Arm 1 • Post Primary Rx (RP or XRT or RP + XRT) • PSADT ≤ 12 mos Sipuleucel-T ADT • Non-Metastatic (bone and CT scan) N = 30 Stratification Immune 18-mos • PSADT ≤ 3 mos or > 3 mos and ≤ 12 mos Response, visit • RP or XRT or RP + XRT Treatment Arm 2 Safety ADT  Sipuleucel-T N = 30 Primary Objective: To determine whether ADT started before or after sipuleucel-T Primary End Point: Immune response, leads to superior augmentation of immune which will be evaluated with an INF-γ response ELISPOT specific for PA2024ADT = androgen deprivation therapy; RP = radical prostatectomy; XRT = radiation therapy; CT = computed tomography;PSADT = prostate-specific antigen double time; ELISPOT= enzyme-linked immunospot; INF= interferon.Antonarakis et al, 2011.
  59. 59. Combining PD-1 Blockade With TKIs in RCC Orthotopic RENCA Model  Hypoxia Anti-PD-1  High VEGF Levels 10 mg/kg  Growth Inhibition With Sunitinib Days -8 -3 0 3 6 9 Day 12 RENCA Treatment Ends Orthotopic (0.5M Cells) Sunitinib 40 mg/kg dailyCourtesy of Hans Hammers, MD, PhD.
  60. 60. Tumor ResponseCourtesy of Hans Hammers, MD, PhD.
  61. 61. Antibody Response 14x 49xCourtesy of Hans Hammers, MD, PhD.
  62. 62. Phase I Study Combining Anti-PD-1 With Sunitinib or Pazopanib in Patients With Metastatic RCC Metastatic RCC Arm S Escalation Arm S Expansion MTD (Prior Pazopanib) Sunitinib + BMS-936558 Sunitinib + BMS-936558 Metastatic RCC Arm P Escalation Arm P Expansion MTD (Prior Sunitinib) Pazopanib + BMS-936558 Pazopanib + BMS-936558 Primary End Points: Safety, Tolerability, MTDMTD = maximum tolerated dose.US NIH, NCT01472081.
  63. 63. Integrating Immunotherapy Into theProstate Cancer Treatment Paradigm 2004 Androgen Docetaxel Ablation Chemotherapy 2010Androgen Docetaxel Ablation Sipuleucel-T Chemotherapy Sipuleucel-T
  64. 64. 2012Androgen Sipuleucel-T Docetaxel Ablation Chemotherapy Sipuleucel-T Abiraterone Cabazitaxel Abiraterone and beyond… Enzalutamide (MDV3100) Iplimumab?
  65. 65. Key Takeaways Sipuleucel-T  In development for kidney – FDA approved in US for cancer CRPC – AGS-003 – Precise MOA under • Randomized phase III investigation ongoing – T cell and antibody data – Anti-PD-1 (BMS-936558) consistent with an adaptive • Phase II dose finding immune response completed In development for prostate • Biomarker study ongoing cancer • TKI combination trial ongoing – ProstVac VF • Phase III ongoing – Anti-CTLA-4 (ipilimumab) • Post-Tax phase III trials ongoing
  66. 66. Case Study: Prostate Cancer Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  67. 67. Clinical States Model Sipuleucel-T Metastatic Disease Cabazitaxel (de novo) Metastatic Metastatic Metastatic Castrate Primary Rising PSA Resistant Castrate Castrate Resistant Resistant Hormone Asymptomatic Disease Symptomatic Post Docetaxel Naive Non-Metastatic Castrate Resistant Docetaxel Abiraterone ADT Enzalutamide (MDV3100)Modified from Scher et al, 2008.
  68. 68. Case Study  64-yr-old man presented with an elevated PSA of 4.5 ng/mL  Negative DRE  Prostate Bx: Gleason 7 (3+4)  4/12 cores positive, all on right  10%–50% of each core involved  Bone scan and CT negative  PMH/PSH: NoneDRE = digital rectal exam; PNBx = prostate needle biopsy; PMH = past medical history; PSH = past surgical history.
  69. 69. Question 1 What would you suggest as primary therapy? 1. RT alone 2. Brachytherapy in combination with RT 3. RT with ADT 4. Primary ADT 5. Radical prostatectomy 6. CryotherapyRT = radiation therapy; ADT = androgen deprivation therapy.NCCN, 2012a.
  70. 70. Case Study (cont.) Patient undergoes radical retropubic prostatectomy – Gleason 7 (3+4) – Organ Confined – Negative Margins – 5/5 LN negative
  71. 71. Question 2 Which subsequent therapy would you choose? 1. Observation 2. Adjuvant RT 3. Adjuvant ADT 4. Clinical TrialNCCN, 2012a.
  72. 72. Case Study (cont.) Course of Treatment  Observed 3 yrs later presents with rising PSA – Post-surgery nadir = 0.1 – 0.2, 0.2, 0.5  Referred to radiation oncology  Salvage RT (66 Gy over 8 wks) – Well toleratedNCCN, 2012a.
  73. 73. Case Study (cont.) Course of Treatment  Post RT PSA continues to rise 3 mos post RT = 2.3 6 mos = 7.0 9 mos = 16.5  Asymptomatic – CT scan = negative for recurrent or progressive disease – Bone scan = negative for evidence of metastasesNCCN, 2012a.
  74. 74. Question 3 What would you recommend at this time? 1. Continued observation 2. Initiate intermittent androgen ablation 3. Initiate continuous androgen ablation 4. Refer for Sipuleucel-T 5. Refer for clinical trialNCCN, 2012a.
  75. 75. Case Study (cont.) Course of Treatment  Based on rapidly rising PSA (doubling time < 12 mos), patient starts continuous androgen-ablation  3 mos later PSA nadirs at 0.4 – Stable x 2 yrs – 2 yrs 3 mos 1.2 – 2 yrs 6 mos 3.5 – 2 yrs 9 mos 11.2  Bone scan + (3 small rib lesions, R femur)NCCN, 2012a.
  76. 76. Question 4 Current recommendation? Asymptomatic, mCRPC 1. Switch bicalutamide to nilutamide 2. DC bicalutamide (antiandrogen withdrawal) 3. Ketoconazole + hydrocortisone 4. Abiraterone acetate 5. Sipuleucel-T 6. Docetaxel chemotherapyNCCN, 2012a.
  77. 77. Case Study (cont.) Course of Treatment  Patient choses Rx with Sipuleucel-T  PSA continues to rise  What is next treatment modality? – Abiraterone acetate + prednisone – Enzalutamide (MDV3100) – Docetaxel + prednisone – CabazitaxelNCCN, 2012a.
  78. 78. Clinical States Model Sipuleucel-T Metastatic Disease Cabazitaxel (de novo) Metastatic Metastatic Metastatic Rising PSA Castrate Castrate Castrate Primary Resistant Resistant Resistant Hormone Asymptomatic Symptomatic Post Docetaxel Disease Naive Non-Metastatic Castrate Resistant Docetaxel Abiraterone ADT Enzalutamide (MDV3100)Modified from Scher et al, 2008.
  79. 79. Immuno-Oncology: Melanoma Jedd D. Wolchok, MD, PhDMemorial Sloan-Kettering Cancer Center
  80. 80. Agents Used for Cancer Immunotherapy  Immune modulators  Vaccines – BCG (bladder cancer) – Hepatitis vaccine – Alpha interferon (melanoma, – HPV vaccine kidney, leukemia) – BCG? – IL-2 (melanoma, kidney  Adoptive cellular therapy cancer) – Allogeneic bone marrow – CTLA-4 blockade transplant  Monoclonal antibodies – Anti-CD20, CD19 (lymphoma) – Anti-HER2 (breast cancer) – Anti-EGF receptor (colorectal cancer)BCG = Bacillus Calmette-Guerin; HPV = human papillomavirus.
  81. 81. High-Dose IL-2 Therapy  RR: 16% (43/270) Probability of Continuing Response (%) 1.0  Durable responses CR (n = 17) PR (n = 26) – Median 8.9 mos 0.8 CR + PR (n = 43) – CR: not reached 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of Response (mos)Atkins et al, 1999.
  82. 82. Ipilimumab, A CTLA-4 Blocking MoAB, Augments T-Cell Activation T-Cell Remains Active T-Cell Activation T-Cell Inactivation CTLA-4 T Cell Resting T Cell T Cell TCR CD28 CTLA-4 CTLA-4 HLA B7 Ipilimumab APC APC APCKorman et al, 2006.
  83. 83. Anti-CTLA-4 and GM-CSF Tumor Cell Vaccine Synergize to Eradicate Established B16 Melanomavan Elsas et al, 1999.
  84. 84. Clinical Response in Melanoma: NCI  Experienced complete resolution of 2 subcutaneous nodules, 31 lung metastases and 0.5 cm brain metastasisPhan et al, 2003.
  85. 85. Immune-Related Adverse Events  Rash (20%)  Colitis/Enteritis (15%)  Elevated AST/ALT (10%)  Thyroiditis (3%–5%)  Adrenal Insufficiency (< 1%)  Hypophysitis (3%–5%) Severity is inversely related to vigilance of surveillance. If detected early, most are easily treated and reversible.Wolchok, 2010.
  86. 86. MDX010-20 Study Schema ≥ 1 Re-Induction Screening Induction (eligible patients) 3:1:1 R A Ipilimumab + gp100 PD Ipilimumab + gp100 Previously N (n = 403) treated, HLA-A2*0201+ D Follow-Up patients with Ipilimumab alone PD Ipilimumab alone O advanced (n = 137) melanoma M (N = 676) I gp100 alone gp100 alone PD Z (n = 136) E Induction: Ipilimumab at 3 mg/kg, with or without gp100, q3wks for 4 treatments Reinduction: Patients with SD for 3 mos’ duration from Wk 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PDHodi et al, 2010.
  87. 87. Kaplan-Meier Analysis of Survival Comparison HR P-value Arm A vs C 0.68 0.0004 Arm B vs C 0.66 0.0026 Arm A vs B 1.04 0.7575 Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) 1 2 Years 3 4 Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-yr 44% 46% 25% 2-yr 22% 24% 14%Hodi et al, 2010.
  88. 88. Study 024: Overall Survival Estimated Survival 1 Yr 2 Yr 3 Yr* Rate Ipilimumab + DTIC 47.3 28.5 20.8 N = 250 Placebo + DTIC 36.3 17.9 12.2 N = 252*3-yr survival was a post-hoc analysis.Wolchok et al, 2011.
  89. 89. 11/28/06 1/9/07Wolchok , 2010.
  90. 90. Ipilimumab Pattern of Response: Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-Treatment Wk 12: Progression July 2006 3 mg/kg Ipilimumab q3wks X 4 New lesions Wk 20: Regression Wk 36: Still RegressingWolchok et al, 2008a.
  91. 91. Four Patterns of Response to Ipilimumab Therapy Were Observed  2 conventional – Response in baseline lesions – SD with slow, steady decline in total tumor volume  2 novel – Response after initial increase in total tumor volume – Response in index plus new lesions at or after the appearance of new lesionsWolchok et al, 2009.
  92. 92. irRC Identifies Survivors in Patients With Progressive Disease by mWHO Pooled data from phase II studies CA184-008 and CA184-022: Ipilimumab monotherapy 10 mg/kg (N = 227)mWHO = modified World Health Oncology criteria.Wolchok et al, 2009.
  93. 93. CTLA-4 Blockade: A Case Study for Immunotherapy in Need of Biomarkers Knowns Unknowns  Clinical benefit for a  Biomarkers for response subset of patients with  Biomarkers for toxicities refractory melanoma  Effect on effector vs  Reversible mechanism- regulatory T cells in based side effects humans  Tumor responses tend to  Antigens recognized after be durable infusion  Kinetics of response  Importance of vaccination unlike cytotoxics before treatment  Relevance of PBMC vs.PBMC = peripheral blood mononuclear cell. tumor site findingsWolchok, 2010.
  94. 94. ALC Correlates With Clinical Benefit Mean longterm ALC 4 clinical benefit 3 ALC [K/mcl] no clinical benefit 2 1 -4 months -3 months -2 months -1 month week 10 week 12 week 24 week 36 week 1 week 4 week 7  This patient population comprises all patients (N = 73) available at the Immune Monitoring Facility of Memorial Sloan-Kettering Cancer Center, New YorkALC = absolute lymphocyte count.Ku et al, 2010.
  95. 95. NY-ESO-1 Antibody and CD4 TCR Were Detected After Full-Length NY-ESO-1 Protein Vaccination % IFNg+ CD4 T Cells Reciprocal Titer NY-ESO-1 recombinant protein NY-ESO-1 peptide poolModified from Adams et al, 2008.
  96. 96. NY-ESO-1 CD4 and CD8 T-Cell Specific Response After CTLA-4 Blockade (Patient IMF-11) Percent of IFN-g+MIP-1b+ or IFN- g+TNF-a+ T CellsReciprocal Titer IMF-11 Experiencing CR CD8 T Cells CD4 T CellsYuan et al, 2011a.