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How Do We Predict Chemo-Radio Sensitivity?

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How Do We Predict Chemo-Radio Sensitivity? Basic Principles of Tumor Immunotherapy Ezra E. W. Cohen Moores Cancer Center University of California San Diego Disclosures • Consulting – Pfizer, Merck, BMS, Amgen, AstraZeneca, Human Longevity Inc. • DMC – GenMab • I will not be discussing non-FDA approved treatments Overview • How cancer and the immune system learn to co-exist • Potential immune related interventions in cancer • Interventions currently being pursued – Checkpoint blockade – Adoptive cell transfer – Vaccines • Toxicity of immunotherapy The promise of immunotherapy: The Kaplan-Meier curve tail Survival (%) Survival Time Chemotherapy Combination with Genomically targeted therapy genomically targeted Immune checkpoint therapy agent and immune checkpoint therapy Sharma P & Allison JP. Cell 2015 Ipilimumab ± Nivolumab in Previously Untreated Metastatic Melanoma Death or Disease Median PFS, Progression, n/N Mos (95% CI) Nivolumab plus ipilimumab 30/72 NR Ipilimumab 25/37 4.4 (2.8-5.7) 100 HR: 0.40 (95% CI: 0.23-0.68; P < .001) 90 80 70 Nivolumab plus ipilimumab (n = 72) 60 50 40 30 Ipilimumab (n = 37) PFS (% PFS (% of Pts) 20 10 0 0 3 6 9 12 15 18 Mos Postow MA, et al. N Engl J Med. 2015;372:2006-2017. Fig. 3 The cancer immunoediting concept. Robert D. Schreiber et al. Science 2011;331:1565-1570 Published by AAAS Curr Opin Immunol. 2014 Apr;27:16-25 Curr Opin Immunol. 2014 Apr;27:16-25 Curr Opin Immunol. 2014 Apr;27:16-25 Cancer Immune Cycle Immunity, 39:1–10 Immune Avoidance vs. Immunogenic Escape Oncoimmunology. 2016 Mar; 5(3): e1086862. Types of Cancer Antigens Stem cell antigens not present in cells after birth but abnormally expressed in cancer Antigens due to somatic mutations in DNA RNA Post-translational modification Isoform antigens made by abnormal Inflammation mRNA splicing Neo-Antigens made by during abnormal post- exaggerated translational Bacteria cellular proliferation modification of proteins, Virus including glycosylation Neo-antigens generated and phosphorylation by oxidation and Viral and deamination during bacterial chronic inflammation antigens Checkpoint Blockade Checkpoint Blockade (Signal 2) ? ActivationActivation && ProliferationProliferation T-cell T-cell X TCR PD-1 TCR PD-1 CD28 CD28 B7 PDL1/2 B7 MHC MHC Anti PD-1 Antibody APC APC Pardoll DM, Nature Reviews Cancer 12, 252- Page . 15 264 (April 2012) Sharabi A. et al., J Rad Onc, 2013 Pembrolizumab Antitumor Activity 100 Melanoma[1] (N = 411) 100 NSCLC[2] (N = 262) 100 HNSCC[3] (N = 61) 80 KEYNOTE-001 80 KEYNOTE-001 80 KEYNOTE-012 60 60 60 40 40 40 20 20 20 0 0 0 -20 -20 -20 -40 -40 -40 -60 -60 -60 -80 -80 -80 of Target Lesions(%) of Target Change From Baseline -100 -100 -100 in of Sum LargestDiameter Urothelial Cancer[4] Gastric Cancer[5] TNBC[6] (N = 32) cHL[7] (N = 29) 100 (N = 33) 100 (N = 39) 100 KEYNOTE-012 100 KEYNOTE-013 80 KEYNOTE-012 80 KEYNOTE-012 80 80 60 60 60 60 40 40 40 40 20 20 20 20 0 0 0 0 -20 -20 -20 -20 -40 -40 -40 -40 -60 -60 -60 -60 -80 -80 -80 -80 of Target Lesions(%) of Target Change From Baseline -100 -100 -100 -100 in of DiameterSumLargest 1. Robert C, et al. Lancet. 2014;384:1109-1117. 2. Garon EB, et al. ESMO 2014. LBA43. 3. Chow LQ, et al. ESMO 2014. LBA31. 4. O’Donnell P, et al. ASCO GU 2015. Abstract 296. 5. Muro K, et al. ASCO GI 2015. Abstract 03. 6. Nanda R, et al. SABCS 2014. Abstract S1-09. 7. Moskowitz C, et al. ASH 2014. Abstract 290. Adoptive Cell Transfer Fig. 1 General schema for using the adoptive cell transfer of naturally occurring autologous TILs. Steven A. Rosenberg, and Nicholas P. Restifo Science 2015;348:62-68 Published by AAAS Fig. 3 A “blueprint” for the treatment of patients with T cells recognizing tumor-specific mutations. Steven A. Rosenberg, and Nicholas P. Restifo Science 2015;348:62-68 Published by AAAS Fig. 4 Gene-modification of peripheral blood lymphocytes. Steven A. Rosenberg, and Nicholas P. Restifo Science 2015;348:62-68 Published by AAAS Neoantigen Based Vaccines Neoantigen-based Immunotherapy Cancer patient (NED/MRD) 2 mg tissue (FNA) & 2 ml PBL Obtainable at outpatient clinic Tumor biopsy + PBL 100x WES +RNAseq 14 day turnaround Genomic Sequencing Expressed mutations identified Unbiased approach (No epitope Bioinformatic analysis prediction algorithm) Immunological Analysis ELISPOT and multimer-based detection Uses fresh or cryopreserved PBL/pheresis or TIL “Cancer Mutanome” 14 day turnaround Basis for personalized vaccine and immunotherapy Combination Therapy Tumor Cell IFN-γ–mediated IFN-γR upregulation of tumor PD-L1 PD-L1/PD-1–mediated inhibition of tumor cell killing IFN-γ Priming and activation of T cells Other NFκB P13K Dendritic CD8+ cytoxic Cell T lymphocyte PD-1 IDO PD-L1 PD-L2 Treg TGF-β Tumor-associated cell Immune cell T-cell receptor fibroblast modulation of T cells M2 Th2 MHC-1 macrophage T cell CD28 Stromal PD-L1 PD-L2–mediated inhibition of T 2 T cells Shp-2 modulation of T cells CSF-1R H B7.1 Clin Cancer Res. 19:1021-1034. Checkpoint Blockade Toxicity J Clin Oncol 2012; 30:2691-7. CONCLUSIONS • Tremendous excitement about immunotherapy in cancer • Predicated on a better understanding of the interactions between the immune system and tumor • Immunotherapy now represents standard of care for several cancers • Specific considerations need to be remembered – Efficacy – Toxicity Oncology Redux Before Immunotherapy After Immunotherapy.
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