Combining ADCs with Immuno-Oncology Agents Chad May, PhD Senior Director Targeted Immunotherapy Oncology Research Unit, Pfizer 7 th Annual World ADC October 10, 2016
Cancer-Immunity Cycle Innate Immunity Adaptive Immunity Pfizer Confidential For internal use only - 2 Chen & Mellman. Cell (2013)
Cellular Infiltrates Within the Tumor Microenvironment Pfizer Confidential For internal use only - 3 Kerkar & Restifo. Cancer Research (2012)
How Do CD8+ T-cells Recognize Tumors? Major Histocompatibility Complex (MHC) Antigen presenting cell (APC) Pfizer Confidential For internal use only - 4 Yewdell, et al. Nature Reviews Immunology (2003)
How Do CD8+ T-cells Recognize Tumors? Release Cytotoxic Proteins T-cell Receptor (TCR) Major Histocompatibility Complex (MHC) Antigen presenting cell (APC) Pfizer Confidential For internal use only - 5 Yewdell, et al. Nature Reviews Immunology (2003)
Tumor Antigen Mediated T-cell Activation Pfizer Confidential For internal use only - 6 Kurts, et al. Nature Reviews Immunology (2010)
Immune Editing Reduces T cell Recognition Pfizer Confidential For internal use only - 7 Schreiber, et al. Science (2011)
Immune Checkpoints Regulate the Immune Response Pardoll, Nature Reviews Cancer 2012 Pfizer Confidential For internal use only - 8
Check Point Blockade May Restore T cell Recognition Anti-CTLA-4 Anti-PD-1/PD-L1 Pfizer Confidential For internal use only - 9 Kurts, et al. Nature Reviews Immunology (2010)
Disease Control Emerging Treatment Paradigms in Oncology 100% Immunogenic Cell Death DC maturation ADCs + IOs? ADC Payloads Calicheamicin, MTIs, etc 20-30% Immuno-Oncology BTx αctla-4, αpd-1, αpd-l1 Targeted Therapies Time Cytotoxics ADCs Gerber, et al. Biochemical Pharmacology (2016) Pfizer Confidential For internal use only - 10
Galon, et al. Science (2006) The Tumor Immune Environment Impacts Response to Chemotherapy Pfizer Confidential For internal use only - 11
Immune Infiltration in the Tumor Impacts Response to Chemotherapy Halama, et al. Cancer Research (2011) Pfizer Confidential For internal use only - 12
The Local Immune Environment Impacts Response to Chemotherapy Ray-Coquard, et al. Cancer Research (2009) Pfizer Confidential For internal use only - 13
Combining ADCs with Immunotherapies Melero, et al. Nature Reviews Cancer (2015) Pfizer Confidential For internal use only - 14
Tumors Prevent Dendritic Cell Maturation Almand et al. The Journal of Immunology (2001) Ghiringhelli, et al. Journal of Experimental Medicine (2005) Pfizer Confidential For internal use only - 15 Comabella, et al. Nat Rev Neurol (2010)
Immunogenic Cell Death Improves T-cell Recognition Immunogenic Cell Death Dendritic Cell Maturation + αctla-4 + αpd-l1 or αpd-1 Modified from Galluzzi, et al. Nature Reviews Drug Discovery (2012) Pfizer Confidential For internal use only - 16
ICD Induced DAMPs Damage-Associated Molecular Patterns (DAMPs): Calreticulin Endoplasmic reticulum chaperone Exposed on the cell surface in the course of ICD Phagocytic signal to professional APCs such as dendritic cells HMGB1 Nuclear protein released from cells undergoing ICD Mediates proinflammatory effects upon binding to immune cell receptors (i.e. TLRs) Promotes chemotaxis ATP Acts as a strong chemoattractant and promotes the recruitment of immune cells Stimulates proinflammatory cytokine release Bianchi ME, Cell Death and Differentiation (2014) Pfizer Confidential For internal use only - 17
Screening of Novel Inducers of ICD In Vitro Calreticulin HMGB1 ATP Sukkurwalaabc, et al. Oncoimmunology (2014) Pfizer Confidential For internal use only - 18
Assays for the Evaluation of ICD In Vivo Vaccination assays Kepp, et al. OncoImmunology (2014) Pfizer Confidential For internal use only - 19
Assays for the Evaluation of ICD In Vivo Therapeutic assays Kepp, et al. OncoImmunology (2014) Pfizer Confidential For internal use only - 20
Screening of Novel Immunogenic Cell Death Inducers Septacidin-killed MCA205 cells protected 4/5 (80%) C57BL/6 mice against tumor rechallenge Previous reports: oxaliplatin 80% protection doxorubicin 90% protection mitoxantrone 80% protection Sukkurwalaabc, et al. Oncoimmunology (2014) Pfizer Confidential For internal use only - 21
Cardiac Glycosides Exert Anticancer Effects by Inducing ICD Menger, et al. Science Translational Medicine 2012 Pfizer Confidential For internal use only - 22
Deliver ADC Payloads That Induce ICD/DC Activation Microtubulin Inhibtors Martin, et al. Cancer Immunol Immunother (2014) Philipp Müller, et al. Cancer Immunol Res (2014) Philipp Müller, et al. Keystone Symposium (2015) The Antibody-drug-conjugate T-DM1 induces potent anti-tumor immunity in HER2+ breast cancer: Implications for combinations with Immunotherapy Pfizer Confidential For internal use only - 23
Deliver ADC Payloads That Induce ICD/DC Activation Toll like Receptor Agonists Gadd, et al. Bioconjugate Chemistry (2015) Pradere, et al. Oncogene 2014 Pfizer Confidential For internal use only - 24
Deliver Payloads That Induce ICD/DC Activation Shir, et al. Clinical Cancer Research (2010) Edinger, et al. PLOS One (2016) Pfizer Confidential For internal use only - 25
Limitations of Immunocompetent Mouse Models Syngeneic transplantable models Limited tumor models that are not well characterized Most models lack tumor stromal architecture Strain to strain variability in immune response Genetically engineered mouse models Better recapitulates the multiple steps of tumorigenesis resulting in a more relevant tumor architecture They lack high mutational loads therefore less likely to generate tumor neo-antigen specific T-cell responses Often lack optimized surrogate anti-mouse biotherapeutics Mouse cross reactive biotherapeutics can generate antidrug antibody responses limits exposure anaphylaxis Pfizer Confidential For internal use only - 26
Limitations of Immunodeficient Mouse Models Adoptive immune cell transfer Study one immune cell type in isolation (T-cell, NK cell, etc) Potential for anti-mouse activity Challenge to maintain certain immune cell types in vivo Since immune cells and tumor are most often not HLA matched immune responses after treatment may be an allograft response and not against tumor specific neo-antigens Humanized mice Stable engraftment of many immune cell subtypes, but only a limited number fully mature Since immune cells and tumor are most often not HLA matched immune responses after treatment may be an allograft response and not against tumor specific neo-antigens Pfizer Confidential For internal use only - 27
How Predictive Will Pre-Clinical Models Be? Efficacy seen using preclinical in vivo models has translated into the clinic for specific immunotherapies, such as anti-ctla-4 and anti-pd-1/pd-l1 but it is still unclear how successful other IO therapeutics will be in patients. As more therapeutic modalities enter the clinic that target the various immune cell types we will get a better understanding of which preclinical models are more predictive. Because of each model s limitations, predicting single agent efficacy is challenging, therefore combining immunotherapies with ADCs is much more complicated and it may be more difficult to predict success using preclinical models. Pfizer Confidential For internal use only - 28
Cytotoxic Agents May Inhibit T cell Activation and Expansion The choice of chemotherapeutic agent and timing of these combinations will be important, because many cytotoxic chemotherapeutics target rapidly dividing cells. Chemotherapy regimens that deplete proliferating lymphocytes may negatively affect the efficacy of IO therapeutics, which act by facilitating the activation and proliferation of tumor-infiltrating lymphocytes. Mahoney, et al. Nature Reviews Drug Discovery (2015) Litterman, et al. The Journal of Immunology (2014) Kang, et al. The Journal of Nursing (2009) Pfizer Confidential For internal use only - 29
Examples of ADC + IO Combinations in the Clinic Seattle Genetics Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma Nivolumab and Brentuximab Vedotin in Treating Older Patients With Untreated Hodgkin Lymphoma A Study of Brentuximab Vedotin Combined With Nivolumab for Relapsed or Refractory Hodgkin Lymphoma A Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas AbbVie: ABBV-085, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors Immunogen: Study of IMGN853 in Comb. With Bevacizumab, Carboplatin, PLD or Pembrolizumab in Adults With FRa + Adv. EOC, Primary Peritoneal, Fallopian Tube, or Endometrial Cancer Roche: Safety and Pharmacokinetics of Atezolizumab in Combination With Trastuzumab Emtansine or With Trastuzumab and Pertuzumab in Participants With HER2-Positive Breast Cancer Pfizer Confidential For internal use only - 30
Single Agent Safety Important for IO Combos Doublets and triplets will be part of future IO combo treatments Melanoma Ph3: Ipilimumab + dacarbazine (DNA alkylator) Combination increased liver toxicity (56% Grade 3 or 4) IO combos can lead to increased colitis, hepatitis, dermatitis Chemo vs targeted vs ADC + IO ADCs may replace chemo for better safety (liver, GI) ADCs may replace targeted (mabs) for better efficacy Goal: Improved safety & efficacy of BioTx vs SOCs + IO Pfizer Confidential For internal use only - 31
ADC + IO Combinations: Beyond CTLA-4 and PD-1 T cell activation is a multiple-signal process Kershaw, et al. Nature Reviews Cancer (2013) Pfizer Confidential For internal use only - 32 Mahoney, et al. Nature Reviews Drug Discovery (2015)
Tumor Microenvironment Inhibits T-cell Activity Myeloid Derived Suppresser Cell Tumor Associated Macrophage Regulatory T cell Fibroblast Immature Dendritic Cell Pfizer Confidential For internal use only - 33
Next Generation ADCs to Directly Target Immune and stromal Cells Myeloid Derived Suppresser Cell Tumor Associated Macrophage Regulatory T cell Fibroblast Immature Dendritic Cell > Tumor recognition Pfizer Confidential For internal use only - 34
ADC + IO Outlook Hypothesis: ADC & IO will increase durability of response and percent of patients benefiting from IO How we pick the winners for ADC & IO combos? Active ADC in early stage clinical development Correlation between target expression and response rates ADCs vs chemo for IO combinations Avoiding overlap in toxicity profiles: Liver & GI toxicity Explore sequential dosing to avoid interference with TILs Preclinical evidence in support of hypothesis Translational clinical studies looking at IO targets, ICD induction Biological rationale in support of complementary MOAs Recruitment of CD8 T-cells into the tumor Immunogenic cell death (ICD), dendritic cell activation Inflammatory tumor microenvironment Pfizer Confidential For internal use only - 35