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Principles of Tumour Immunology Principles of tumour immunology Michele Teng Nov 20th 2017, Singapore Cancer Immunoregulation and Immunotherapy Laboratory QIMR Berghofer MRI Brisbane, Australia [email protected] Disclosure Slide • I have received speakers bureau honoria from Merck Sharp & Dohme. Talk Outline 1. Hallmarks of Cancer 2. Cells of the Immune system 3. The Cancer Immunity Cycle - Tumor-associated antigens (TAA), Cellular and Humoral responses to TAA 4. Conceptual developments in the field of tumour immunology - Immunosurveillance and role of innate immunity, immune balance against cancer Sources of slide • Charles Janeway’s Immunobiology text book • Peer-reviewed articles (Pubmed) • Online slides ( URL listed) Cancer Hallmarks of Cancer (2000) Hanahan and Weinberg, Cell 2000 Emerging Hallmarks and Enabling Characteristics Hanahan and Weinberg, Cell 2011 Hallmarks of Cancer (2017) In Vitrogen Immunology (Study of the immune system) Cells of the immune system ILCs –innate lymphoid cells MAITs –Mucosal associated invariant T cells gd T cells – gamma delta T cells (ILCs) (gd, MAIT) Cancer Immunology (Study of the response of the immune system to cancer) The Cancer-Immunity Cycle – Steps to generate an effective anti-tumour response Chen and Mellman Immunity 2013 Not all cell deaths are equal (at priming an immune response) Cells can die in different ways DAMPs Tumour fragments Immunogenic Cell Death (ICD) DAMPs – Damage (Adjuvanticity, Antigenicity) associated molecular patterns Differential requirements for the immunogenicity of cell death TLR4 Nat Rev Immunol. 2017 Feb;17(2):97-111. doi: 10.1038/nri.2016.107. The Cancer-Immunity Cycle Immunity. 2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012. Types of professional Antigen Presenting Cells (APCs) Nat Rev Immunol. 2014 Nov;14(11):719-30. doi: 10.1038/nri3754. Activation of tumour-specific T cells by APCs TCR with the right specificity Tumor-specific and tumor-associated antigens (Neoantigens) © QIMR Berghofer Medical Research Institute | 19 TAA – therapeutic targets? Cell-mediated and humoral immune responses to tumour Requirements for effective priming of T cells Front. Oncol., 10 April 2014 | https://doi.org/10.3389/fonc.2014.00077 The many flavours of CD4+ T cells Th22 Cell-mediated and humoral immune responses to tumour T cell-independent and T cell-dependent B cell activation Antibody mechanism of action IgG1 FcgRIIIa -activating receptor NK cells Antibody mechanism of action Activate cellular effector function Antibody-Dependent Antibody-Dependent Cell-Mediated Cytotoxicity Cellular Phagocytosis Biolegend ADCC - the underlying mechanism for the clinical efficacy of therapeutic anti-cancer antibodies. Biolegend Effector responses of NK cells are regulated by inhibitory and activatory receptors Release of Cytokines Cytolysis Trends in Immunology 2011 32, 364-372DOI: (10.1016/j.it.2011.06.001) Major inhibitory and activating receptors on NK cells and their cognate ligands on targets NKp30 isoforms predict clinical outcome of GIST, neuroblastoma Chan et al., 2014 Cell Death Differentiation The Cancer-Immunity Cycle Immunity. 2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012. When the Cancer Immunity Cycle is successfully completed…… Cancer Immunology (pre 2000) Reason for failures Cancer Immunology (2000-2017) - What went right.... Conceptual Developments in Cancer Immunology 1Cancer 2Tumour immunoediting Neoantigen 4Combination mAb-based therapy 3Immune Reaction 5Tumour induced Immune suppression 1 3Es KILL BATTLE LOSE Smyth et al. JEM 2000, Shankaran et al. Nature 2001 Swann et al. J. Clin. Invest. 2007, Koebel et al. Nature 2007 Teng et al., JLB 2008; Schreiber..Smyth. Science 2011 Teng et al., Cancer© ResQIMR 2012,Berghofer Teng Medical et al.,Research JCI 2015Institute | 36 2Mutational load correlates with frequency of tumour neoantigens... & response Estimate of the neoantigen repertoire in human cancer MHC Synder A et al., NEJM 2014 Ton N. Schumacher, and Robert D. Schreiber Quality van Allen et al., Science , 2015, Hugo W et al., Cell 2016 Science 2015;348:69-74 3 Immune contexture correlates with clinical outcome NKT Stroma Neutrophil B cells Immune contexture Mast cell Location, density, functional associated with good orientation of cells prognosis in CRC Blood Eosinophil vesse Macrophage Chemokine l Immature NK CTL ↑CXCL9 ↑CX3CL1 DC ↑ CXCL10 ↑ CCL2 T 17 ↑ CCL5 ↑ CXCL13 Tumor H γδT core MDSC Adhesion ↑MADCAM1 ↑ ICAM1 Treg ↑ VCAM1 DC TFH Cytotoxic F-DC ↑ Granzymes TH1 Invasive ↑ Perforin Lymphaic margin ↑ Granulysin vessel TH1 TH1 TH1 ↑T-bet ↑ IL-12 Epithelial/smooth ↑ IRF1 ↑ IFN-γ TLS muscle layer ↑ STAT1 ↑IL-15 B TFH ↑ IL21 cells Tumor margin ↑ CD3+, CD8+, Immunoscore CD45RO+ T cells Galon et al., 2006 Science, Pages et al., 2005 NEJM, Fridman et al., 2012 NRC, Bindea el al., 2013 Immunity Mechanism of Treg mediated immunosuppression Worman C et al., Cell Mol Life Sci 2009 Mechanism of MDSC mediated immunosuppression Dmitry I. Gabrilovich Cancer Immunol Res 2017;5:3-8 4 (trimAb) trimAb anti-DR5 (immunogenic cell death) anti-CD40 (activate APC) anti-CD137 (enhance effector T cell function and survival) MCA induced fibrosarcoma model MCA Detect sarcoma 50-180 d Measure growth Commence treatment WT or KO mouse Rejection of carcinogen-induced established tumors by trimAb Uno et al. Nature Medicine, 2006 4 The four nodes to target for inducing maximal anti-tumour immunity Smyth et al., NRCO 2016 5 Engagement of checkpoint receptors represents a major mechanism of tumour-induced immunosuppression Checkpoint receptors: Brakes to limit overzealous T cell activation About 20 interactions regulate T cell immune response Melero I et al. APC/Tumour T cell Nat Rev Cancer 2015 Checkpoint blockade can unleash endogenous anti-tumour response ORR – 10% 2010 ORR – 31% 2012 ORR – 53% 2013 ORR – 61% 2015 Anti-PD-1 to be used as standard of care and in combination immunotherapies ORR – 2015 33.7% vs 11.9% ORR – 2015 31.7% vs 10.6% ORR – 20% vs 9% 2015 ORR – 2016 44.8% vs 27.8% Cancer immunotherapy-based combination studies underway in 2016 Chen & Mellman Nature 2017 Tumour microenvironment can be stratified into 4 types based on TILs and PD-L1 expression in tumours Teng et al., 2015 Cancer Res Summary • Anti-PD-1/PD-L1 - will become the immunotherapeutic backbone of future cancer treatments • Cancers can be divided into four type – absence or presence of TILs and PD-L1 expression • Efficient anti-tumour strategies must focus on hitting different targets concurrently • Key nodes to target in combination treatment – abrogating immune suppression – inducing immunogenic cancer-cell death, – enhancing antigen presentation/adjuvanticity – inducing activation and survival of immune-effector cells Summary • Exome-sequencing data can be mined to – identify unique neoantigen profile of tumours – guide future personalized vaccine design for use in combination treatments • A large proportion of patients have ‘immune ignorant’ (cold) tumours, – predicted to have a poor prognosis regardless of any current intervention – novel therapies have to be developed (Oncolytic virus, STING agonist, CAR-T). Moving Forward… Key issues in cancer immunotherapy 1) Identifying biomarkers to predict what cancers and pts will respond to anti-PD-1/PD-L1 2) How do we increase the proportion of patients who respond to anti-PD-1/PD-L1? 3) What therapies do we use to treat cancers with microenvironments that are resistant to anti-PD-1/PD- L1 monotherapy? 4) What do we do for patients who develop acquired resistance to anti-PD-1 therapies? 5) What is the optimal scheduling for administration of combination immunotherapy? 6) How to assess the therapeutic index (anti-tumour efficacy/irAEs) of combination immunotherapies? Improving the tail of the curve.... Overall Survival Overall Time Thank You www.qimrberghofer.edu.au Identifying biomarkers to predict patients who will respond to anti-PD-1/PD-L1 Tumour microenvironment can be stratified into 4 types based on TILs and PD-L1 expression in tumours TIL+ TIL- PD-L1+ PD-L1- (38%) (41%) Type I Type II Melanoma Type IV Type III TIL+ TIL- PD-L1- PD-L1+ (20%) (1%) Taube et al. Sci Transl Med 2012, CCR 2014 Association of anti-PD-L1 response and tumour-infiltrating immune cell PD-L1 expression Nature, 2014 Cancers with type I TME containing CD8+ T cells and PD-L1 most likely to respond to anti-PD-1/PD-L1 Level of PD-1 expression Ngiow et al., Cancer Res 2015 PDL2 expression? Tumeh et al. Nature (2014) © QIMR Berghofer Medical Research Institute | 59 Factors that influence the cancer–immune set point Biomarkers of response to PD-1/PDL1 blockade Density, Location PD-1 expression level Other checkpoint Angiogenesis receptors Epigenetics Other immune cells CD8+ T cell Tumor/Immune Microbiome MMR-deficient/MSI-H cells Somatic vs Driver IFN gene signature mutations (early on txt) (e.g BrafV600) Mutational PD-L1 Burden expressio n Tumor load Genetics Age External factors Prior therapy Time Durability of Response From bed-side To bed-side Clinical research Ex vivo/ Experimental In vitro research Mouse research To bench From bench © QIMR Berghofer Medical Research Institute | 62 Immunotherapy and GI cancer Melero I et al., Abstract presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Atezolizumab (anti-PD-L1) – Tecentriq, approved for treatment of bladder cancer Adaptive immune gene signature in early-on- treatment samples best predict responders Chen, P, Cancer Discov, 2016 • EDT – median 1.4 months (0.7-26 months) • Vilain et al EJC 2015; EDT (within 2 months of treatment) increase in intratumoral CD3+, CD8+, CD68+ in responders • Non-responders – increased VEGFA Checkpoint immunotherapy: picking a winner Teng et al., Cancer Discovery 2016 in press How do we increase the proportion of patients who respond to anti-PD-1/PD-L1? Can we improve above the 50% ORR induced by anti-CTLA-4 & anti-PD-1?* *Without the toxicity Combination of anti-PD-1 or anti-CTLA-4 with IDO inhibitors (Indoximod) in melanoma Abstract #3075 ASCO 2016, Yousef Zakharia.
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