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Immunotherapy !!" !# Hormonal control of androgen pathways and sites of action of PCa therapies Testis Negative feedback control Testosterone (95%) LHRH receptor agonists/ LH GnRH antagonists Orchiectomy Androgen Hypothalamus estrogens receptor Pulsatile GnRH Pituitary AAs ACTH release Prostate Adrenal glands Negative feedback control Adrenal androgens (5%) ACTH, adrenocorticotrophic hormone; FSH, follicle-stimulating hormone; LH, luteinising hormone 4 Drudge-Coates. Int J Urol Nurs 2009;3:85-92 Chronology of FDA Approvals, CRPC Docetaxel Abiraterone + + Prednisone Prednisone Post-Docetaxel Abiraterone % + Prednisone Pre-Docetaxel #$ "! ! 1981 1993 1996 1997 2002 2004 2010 2011 2012 2013 Estramustine Cabazitaxel Enzalutamide + Post- Prednisone Docetaxel Adapted from Gomella Biologic Mechanisms Driving CRPC Antonarakis and Armstrong, Clin Oncol News 2011 Galeterone: Selective, Multi-targeted, Small Molecule for Treatment of CRPC CYP17 Lyase Inhibitor AR Antagonist AR Degrader Inhibits androgen synthesis Blocks androgen binding Decreases AR levels Abiraterone Enzalutamide • No mandatory steroids • Not a GABAA antagonist • Active in C-terminal loss Galeterone • Fasting not required • No seizures AR splice variants • Preclinical activity in • Preclinical activity in mutation T878A mutation F876L 11 In-licensed from the University of Maryland, Baltimore. Galeterone in Four Castrate Resistant Prostate Cancer (CRPC) Populations: Results from ARMOR2 M-E Taplin1, KN Chi2, F Chu3, J Cochran4, WJ Edenfield5, M Eisenberger6, U Emmenegger7, EI Heath8, A Hussain6, A Koletsky9, D Lipsitz10, L Nordquist11, R Pili12, M Rettig13, O Sartor14, ND Shore15, R Dhillon16, J Roberts16, B Montgomery17 1Boston, MA/US, 2Vancouver/CA, 3San Bernardino, CA/US, 4Dallas, TX/US, 5Greenville, SC/US, 6Baltimore, MD/US, 7Toronto/CA, 8Detroit, MI/US, 9Boca Raton, FL/US, 10Concord, NC/US, 11Omaha, NE/US, 12Buffalo, NY/US, 13Los Angeles, CA/US, 14New Orleans, LA/US, 15Myrtle Beach, SC/US, 16Cambridge, MA/US, 17Seattle, WA/US 12 The Renaissance of Immunotherapy Enthusiasm Phase Skepticism Phase Renaissance Phase 1978-1985 1985-1997 1997- 2010 1986 1997 1st cellular IFN-α 1st mAB immunotherapy 1985 (cytokine) approved approved for CA 1st study with approved for 1976 for CA adoptive T-cell CA 1st study transfer in CA 1890s with BCG in 1st CA bladder CA vaccine developed (Coley) 1990s Discovery of 1978 2011 checkpoint 1st checkpoint Discovery inhibitor inhibitor 1973 of tumor (Allison) 1998 Discovery specific IL-2 (cytokine) approved of the mABs approved for CA dendritic cell for CA (Steinman) # #""(#'#"$%%&$%&& BCG, Bacille Calmette-Guerin; mABs, monoclonal antibodies; CA, cancer; IFN-α, interferon alpha; IL-2, interleukin-2 1. Kirkwood JM, et al. CA Cancer J Clin. 2012;62(5):309-335. 3. Krummel MF, et al. J Exp Med. 1995;182(2):459-465. 2. Lesterhuis WJ, et al. Nat Rev Drug Discov. 2011;10(8):591-600. 4. Cheson BD, et al. N Engl J Med. 2008;359(6):613-626. 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 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. 6 % " ! ) % -& ! .& ' ( ! ) * + "% -& " .& " " " " " " " $ & $ & &/&.,--& Immune Checkpoint Inhibitors clinicaloptions.com/oncology General Approaches for Cancer Immunotherapy Peptide vaccine DC vaccine CD40 Genetic vaccine CD137 IL-2 IFN OX40 IL-15 IL-21 CTLA-4 Active immunotherapy Adoptive cell transfer PD-1 immunotherapy TCR or CAR T cell cloning genetic engineering Ribas A. N Engl J Med 2012;366:2517-2519. 8 9 • ! • ! ! • " # • !!$ Evolution of Breakthrough Therapeutic Modalities in Cancer ADCC Innate Immunotherapy mAbs NK Therapy Adaptive Immunotherapy CAR-T Therapy Antibody • Binds directly to antigens NK Cell • Often dependent on patient T-Cell immune system for effect • Innate • Learned (Adaptive) • Always switched on • Requires switching on • Multiple modes of killing • Delayed killing o Innate direct killing o Antibody-mediated killing o Tumor-targeted killing " ! A Living Killing Machine: NK Cell Innate Immune Protector Adhesion & Targeting Receptors Targets and binds to tumor cell 1 & tumor cell matrix, and viral infected cells CD2 Innate Direct Killing CD69 CD94 Innate CARs Autologous NKG2 Natural Killer Cell NKG2D (NK Cell) 2B4 CD16 NKp30, 44, 46 LFA-1 NantKwest Unique NK Cell: Activated Natural Killer (The aNK Cell) Adhesion & Targeting Receptors Inhibitory Receptors (KIRS) Targets and binds to tumor cell 7 Turns off cell killing 1 & tumor cell matrix, and viral infected cells CD2 Innate Direct Killing CD69 CD94 Antibody Mediated Killing NKG2 Off the Shelf Binds to Antibodies NKG2D Activated Natural 6 Activates cell death (ADCC) 2B4 Killer Cell Activation Receptors CD16 (aNK) Triggers release of killing 2 mechanism NKp30, 44, 46 LFA-1 Release of Chemokines Targeted Killing 3 Attracts killer T-Cells Release of Perforin & Granzyme 5 Direct cell killing & targeted killing Release of Cytokines 4 Induces apoptosis A Next Generation Immuno Therapy Platform: A Living Drug - Delivered in a Blood Bag with Multiple Modes of Killing Innate Direct Killing CD2 CD69 CD94 NKG2 Universal Off the Shelf NKG2D Activated Natural Killer Cell 2B4 CD16 aNK CD2 CD2 NKp30, 44, 46 CD69 CD69 CD94 CD94 LFA-1 NKG2 NKG2 NKG2D NKG2D 2B4 2B4 CD16 CD16 NKp30, 44, 46 NKp30, 44, 46 Engineered to Engineered to LFA-1 LFA-1 Directly Bind to Directly Bind to Antibodies Target Antigens Antibody Killing Targeted Killing haNK Enhanced Antibody Killing (ADCC) NK Cell (haNK) CD-16 Herceptin Tumor Cell NK vs CAR-T Cells: Key Differentiators NK CAR-T Cells Autologous (patient-derived) Cell Production Off-the-shelf product invasive procedure leukapheresis Transduction GMP Master cell bank Variable CAR transfection & expression Characteristics Multiple MOAs - targeting and Targeting and killing CAR- killing through CAR-dependent MOA dependent and innate mechanisms Anti-Solid Tumor No requirement for additional Require co-stimulators (CD80, CD86) Activity co-stimulation not present in many solid tumors On-target / off-tumor effects less Cytokine release syndrome Safety likely due to short half-life and Prolonged bone-marrow suppression lack of IL-6 production Cardiotoxicity and encephalitis risks Low: large scale bioreactor COGS High: requires individual patient manufacturing for many patients processing .
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