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Harnessing the Power of the Host Immune System to Fight Cancer
Public Harnessing the Power of the Host Immune System to Fight Cancer Robert Kastelein Immuno-Oncology Discovery Texas FreshAIR Conference 2014 Houston October 23-24
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Immunological Homeostasis
T cell receptor B cell receptor NCR CD20 FcR Activation Signal Inhibitory Signal CTLA-4 PD-1 FcR KIRs Cytokines TGFb CD200R TIM3 LAG3 Immunity Homeostasis Costimulatory Signal CD28 CD40 Adhesion molecules Cytokines GITR TIM1 HVEM CD27 Tolerance Joe Phillips, Lewis Lanier
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Role of PD-1 in Chronic Viral Infection
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PD-1 is Important for Immune Tolerance
PD-1 interacts with its ligands (PD-L1 and PD-L2) to inhibit activation of T lymphocytes Cancers can ‘hijack’ the PD-1 pathway PD-1 blockade may reactivate anti-tumor immunity *
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MK-3475 Is a Potent Antagonistic Antibody Against PD-1
First-in-human study of MK-3475 in melanoma (Hamid et al, NEJM 369:134) Expanded study platform – reported activity in NSCLC, H&N cancer, bladder and gastric cancer A signal detection study is exploring activity in 20 different tumor types selected on the basis of PD-L1 expression Sep 4, 2014 – U.S approval of Keytruda for treatment of patients with advanced or unresectable melanoma no longer responding to other treatments
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Best Overall Response in Melanoma Patients Treated with Pembrolizumab (RECIST 1.1)
ORR 34% by RECIST 1.1; 88% of responses ongoing
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Kaplan Meier Estimate of PFS per RECIST 1.1
Public Kaplan Meier Estimate of PFS per RECIST 1.1 69% OS at 12 months; median OS not reached
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Immunotherapy in Oncology: Can we Alter the Survival Curve by Combining Therapies?
Control Checkpoint blockade Standard or other therapy Combination with standard of care or other IMRs
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Placing Immune Interventions in the Context of Tumor Cell Recognition
Public Placing Immune Interventions in the Context of Tumor Cell Recognition Chemokines & homing receptor modulators Cancer vaccines & adjuvants Adoptive T cell therapies Immune checkpoint targets and other immunomodulators Cytotoxic agents Adapted from Chen and Mellman, Immunity 39: 1 (2013)
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Targeting Immunomodulators (IMRs): The Opportunity and the Challenge
By investigating how anti-PD-1 works we will be able to develop meaningful combination strategies Melero I, et al. Clin Cancer Res. 2013;19: ©2013 by American Association for Cancer Research.
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Leveraging Preclinical Data to Inform IMR Selection
Public Leveraging Preclinical Data to Inform IMR Selection Human Clinical Response with MK-3475 Mouse Syngeneic Tumor Models Responder vs. non-responder signature at baseline Post-treatment signatures in responder vs. non-responder Flow cytometry of TILs, markers, IMRs IHC cell markers, IMRs Gene expression in tumors Human Tumor Analysis
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single injection of DX-400
Public Anti-mouse PD1 Surrogate is Efficacious in Multiple, but not all, Syngeneic Tumor Models Subcutaneous CT-26 single injection of DX-400 Initial tumor volumes at start ~100mm3 * Indicates statistical significance
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PD1 and PDL1 are Upregulated Following Anti-PD1 Treatment
DX mpk PDL1 PD1 DX mpk DX mpk DX mpk DX400 5mpk DX400 5mpk
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post anti-PD-1 treatment
Public Anti-PD-1 mAb induced Expansion of Mouse Tumor-associated CD3 and CD8b+ T Cells Control mAb 4 days post anti-PD-1 treatment CD3 CD8 Anti-PD-1 mAb CD3 CD8 MC38 mouse syngeneic tumor model 4 days post anti-PD-1 mAb treatment (DX400; at 5 mg/kg) tumors were analyzed (pink – antigen; blue – nuclei)
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Anti-PD-1 Treatment Elicits Genes Associated with Immune Response (preclinical models)
Cell Marker Anti-Tumor Immune Response Chemokines and Cell Activation/Recruitment M2 and Immuno-Regulatory Profiling Mouse Models: Blood ≠ LN ≠ Tumor
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Intra-tumoral Clonal T-Cell Expansion Following Anti-PD-1 Therapy
mDX400 mDX400 Isotype control Isotype control MC38-tumor bearing mice were treated with 5 mg/kg anti-PD-1. Tumors were harvested at 4 and 9 days following a single mAb dose. Increased intratumoral T cells at 4 and 9 days post-treatment T cell infiltrate is more clonal by 9 days post-treatment Next-generation sequencing and data analyses were performed by Adaptive Biotechnologies.
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Public Glucocorticoid-Induced TNFR-Related protein (GITR) Biology and Target Rationale
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Anti-GITR Treatment Specifically Targets ‘Intra-Tumor’ Tregs
Public Anti-GITR Treatment Specifically Targets ‘Intra-Tumor’ Tregs Innoculate MC38 Anti-mGITR or isotype Analyze TILs and draining LN -8 1 4 12 Day Kinetics of aGITR tx response
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Kinetics of Anti-GITR Treatment Response in Tumor Micro-Environment
Public Kinetics of Anti-GITR Treatment Response in Tumor Micro-Environment Days post anti-GITR treatment 1 4 12 Treg CTL T cells /mg tumor
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Treatment with human GITR Agonist mAb Results in Dose-Dependent Reduction of MLR Induced Regulatory T cells TREGs were induced by stimulating human PBMC with allogeneic dendritic cells for 7 days in the presence of indicated concentrations of anti-human GITR. Treatment with anti-GITR agonist results in significant reduction of FoxP3 TREGs
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Cross-regulation of PD-1 and GITR in vivo
Upregulation of GITR mRNA in tumor after anti-PD-1 treatment Upregulation of PD-1 and PD-L1 mRNA in tumor after anti-GITR treatment PD-1 PD-L1 Min(normalized values) Tumor d1 d4 d8 d12 GITR Differential response Tumor d1 d4 d1 d4 anti-PD-1 isotype d1 d4 d8 d12 Tumor Anti-GITR isotype control Anti-GITR single dose Anti-PD-1 single dose
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Anti-PD-1 + Anti-GITR Combination Efficacy
Large established MC38 tumors used Synergistic combination anti-tumor efficacy observed Combination efficacy observed in additional models All mAbs dosed at 5mg/kg
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Exploiting the Patient’s Immune System for Optimal Anti-Tumor Activity
Public Releasing the brakes anti-CTLA-4 anti-PD-1 antagonists to additional inhibitory IMRs Pushing the accelerator cancer ‘vaccines’ adjuvants (e.g. BCG, TLRs) tumor-specific antigens adoptive immunotherapy cytokines (IL-2, IL-12, IFNa) cellular immunotherapy agonists to immunostim. IMRs – anti-GITR Are both approaches needed for optimal efficacy?
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Acknowledgements MK-3475 team and Anti-GITR team
Public Acknowledgements MK-3475 team and Anti-GITR team Discovery Team (Palo Alto & Boston) especially: Amy Beebe Smita Mauze Renu Jain Ashley Mahne Terri Mcclanahan Svetlana Sadekova Doug Wilson Debbie Law
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