Cancer and the Immune System

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1 NIFA Neue Impulse in Fortbildung und Ausbildung, AstraZeneca Onkologie Symposium, Vienna, October 20 th 2017 Cancer and the Immune System Translational Tumor Immunology Group, Ludwig Cancer Research Center

2 Immunotherapy is definitively becoming mainstream cancer science A rich understanding of the immune system tumor dynamic interactions New cancer treatments targeting the immune system rather than the tumor have entered the standard of care in recent years Thousands of immunotherapy-based clinical trials underway Over papers in PubMed A major endeavor at hospitals, universities and industry

3 Major Questions Can the Immune System recognize Cancer? Can we use the Immune System to fight Cancer?

4 Concept of immunosurveillance

5 The current model of immunoediting: the three Es Elimination Cancer immunosurveillance Effective antigen processing/presentation Effective activation and function of effector cells e.g. T cell activation without co-inhibitory signals Cancer dormancy Genetic instability Tumour heterogeneity Immune selection Equilibrium Cancer progression Tumours avoid elimination through the outgrowth of tumour cells that can suppress, disrupt, or escape the immune system Escape

6 Emerging hallmarks of cancer: avoiding immune destruction Adapted from Hanahan et al. Cell 2011;144:

7 Cancer Immunotherapy Vaccines Adoptive cell transfer 3. Immunomodulating agents Adapted from Rosenberg SA., NEJM 2004

8 Recognition of tumors by the (adaptive) immune system What are the tumor targets recognized by T and B cells?

9 Structure of physiological antigen receptors B CELL RECEPTOR (BCR) T CELL RECEPTOR (TCR) M. Sadelain et al. Nat Rev Cancer 2003

10 T Cell Receptor Membrane Two chains Antibody Membrane and soluble Two H and L chains CDR1, 2 and 3 CDR1, 2 and 3 Ligand: MHC/peptide also unrestricted Two isotypes:, Low affinity (10-5 M) No affinity maturation unrestricted Five classes: M, G, A, D, E Several isotpyes, per class High affinity ( ) Affinity maturation

11 T cell functions Quality control of the internal milieu: - CD4 T cells: extracellular milieu (MHC-II) - CD8 T cells: intracellular milieu (MHC-I) Tissue Homeostasis -Tregs: insulin sensitivity, tissue repair Adaptive immunity -Intracellular parasites (CD8 CTL) -Extracellular pathogens (CD4 Th)

12 Adaptive T cell immune responses (Learning immunology from the LCM virus model) Relative CD8 T cell number Expansion Contraction Memory Virus Days Weeks Years Kaech et al., Cell 2002 Wherry et al., Nat. Immunol., 2003 Kaech et al., Nat. Immunol., 2003 Sarkar et al., J. Exp. Med., 2008

13 Adaptive antitumor immunity Mellman et al. Nature 2011

14 Adaptive specialized CD4 T cell subsets T cell proliferation, tissue inflammation, elimination of extracellular parasites, allergy B cell help in humoral immunity, autoimmunity, immunodeficiency and malignancy Tissue inflammation, bacteria, fungi, autoimmunity and cancer Antigen presentation and cellular immunity Humoral immunity and allergy Mucosal immunity, autoimmunity and cancer Tripathis S. et al. Immunol Rev 2014 Immune suppression/tolarance

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16 CYTOLYTIC CD8 + T LYMPHOCYTES (CTL), the major effectors of anti-tumor adaptive immunity - Direct lysis (perforin, GZB) - IFN-, TNF- GM-CSF - Fas L - CD40L

17 Thérapie par transfert adoptif de TILs CX + FDA Lymphodéplétion Reconstitution J -30 J -7 J 0 TILs IL-2 n = 35 Dudley M et al. 2003, 2005 Expansion rapide + sélection Réponses = 51 % Persistence (télomères)

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19 Engineering T cell antigen specificity by gene transfer M Kalos & C June, Immunity 2013

20 Two CAR T cell products approved by the FDA Kymriah (Novartis) CD19: children and young adult B-cell progenitor ALL refractory or 2x relapsed Yescarta (Kite Pharma) CD19: adults with refractory relapsed large B-cell lymphoma, after 2 lines of Systemic therapy

21 CD8 memory T cell differentiation Relative CD8 T cell number Expansion Contraction Memory Virus Days Weeks Years Kaech et al., Cell 2002 Wherry et al., Nat. Immunol., 2003 Kaech et al., Nat. Immunol., 2003 Sarkar et al., J. Exp. Med., 2008

22 Potent effector functions potential for collateral damage

23 T cells express multiple co-inhibitory receptors upon activation Wherry & Kurachi Nat Rev Immunol 2015

24 Targeting CTLA-4 and PD-1 pathways Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) MHC Dendritic cell B7 B7 TCR TCR CD28 CTLA T cell Anti-CTLA-4 MHC T cell --- PD-1 PD-L1 Anti-PD-1/PD-L1 --- PD-1 PD-L2 Anti-PD-1 CTLA-4 pathway Wolchock J, et al. JCO 2013 Volume 31, Issue 15_suppl ; abstr 9012^ PD-1 pathway Tumour cell

25 Chronic antigen stimulation leads to progressive T cell exhaustion Wherry & Kurachi Nat Rev Immunol 2015

26 What is the evidence that phenotypic and functional heterogeneity of «exhausted» CD8 T cells exist? Intriguing new evidence in support emerging from mouse models of chronic infection

27 At least two subsets of «exhausted» CD8 T cells Terminally differentiated: PD-1 hi Cytokine low, poorly proliferative Memory-like: PD-1 hi Cytokine low, strongly proliferative Utzschneider D et al. Nat Immunol 2013; Speiser et al. Nat Rev Immunol 2015

28 This TCF-1++, CXCR5+, PD-1+ subset has been detected in chronic microbial infection, in mice Do they exist in cancer (mouse, human)? and, if so, do they fulfill the same role?

29 Regulating the T cell immune response 1,2a Activating receptors CD28 OX40 Inhibitory receptors CTLA-4 PD-1 TIM-3 T cell responses are regulated through a complex balance of inhibitory ( checkpoint ) and activating signals Tumours can dysregulate checkpoint and activating pathways, and consequently the immune response CD137 Agonistic antibodies T cell stimulation LAG-3 Antagonistic (blocking) antibodies Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response a The image shows only a selection of the receptors/pathways involved LAG-3 = lymphocyte-activation gene 3 1. Adapted from Mellman I, et al. Nature 2011:480; ; 2. Pardoll DM. Nat Rev Cancer 2012;12:

30 A potential, immune-driven revolution in cancer prevention and control Anti-CTLA-4, approved in 2011 for metastatic melanoma Anti-PD-1, metastatic renal cell carcinoma, 2015 Anti-PD-1, approved in 2014 for metastatic melanoma Anti-PD-1 + anti-ctla-4, met melanoma, 2015 Anti-PD-1, approved in 2015 for metastatic lung carcinoma Anti-PD-1, approved in 2016 for Hodgkin s lymphoma TVEC (HSV-1~GM-CSF), in metastatic melanoma, 2015 Anti-PD-L1, in metastatic urothelial carcinoma, 2016

31 Lessons drawn from these successes Monotherapies with immunodulatory agents significantly improve survival Significant immune related toxicities may occur Measurable responses may be delayed by weeks to months Absence of pre-existing immune responses may predict a poor response to checkpoint inhibitors Biomarkers are needed to guide therapy decisions Vaccines may induce tumor immunity in patients who do not respond to immune modulators (60-70%)

32 A model illustrating the potential impact of single agent and combination cancer immunotherapies on survival Emens L et al. Eur J Cancer 2017

33 One, two, many immune checkpoints PD-1/PD-L1 (CD28), CTLA-4 LAG-3, TIM-3 VISTA, TIGIT, BTLA,

34 One, two, many immunostimulatory receptors CD28 (dose is of the essence!) 41BB, OX40 NKGD, CD27, GITR

35 Tackling additional immunosuppressive loops First in human trials for A2AR antagonist, arginase inhibitor (ASCO 2017) IDO inhibitor (Incyte) in the clinic (Prendergast) Taming, reeducating Tregs (D Vignali) Targeting NK inhibitory receptors: KIRs, Targeting MDSCs: MAPKi, anti-cytokines, chemo Targeting neutrophils: HMGB1 ODN Epigenetic modulatory compounds

36 The adenosine pathway in the tumour microenvironment and tumour progression A2AR CD39 CD73 Antonioli et al. Nat Rev Cancer 2013

37 Metabolic reprogramming during T cell activation Pearce et al., Science 2013

38 Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression Tumor cells and TILs compete for glucose within the tumor niche Metabolic competition can drive cancer progression Checkpoint blockade antibodies alter the metabolic balance in a tumor PD-L1 promotes Akt/mTOR activation and glycolysis in tumor cells Chih-Hao Chang et al. Cell 2015

39 Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses Glucose deprivation suppresses antitumor T cell effector functions Glycolytic metabolite PEP sustains Ca2+ and NFAT signaling by blocking SERCA Ca2+ signaling is an integrator of glycolytic activity and TCR Signaling T cell metabolic reprogramming enhances anti-tumor effector functions (Metabolic rewiring of T cells to generate PEP in glucose-poor conditions) Ping-Chih Ho et al. 2015

40 Key amino acids: Catabolic enzymes: Tryptophane IDO, TDO Arginine Arginase Phenylalanine Phenylalanine oxidase (IL4I1) Glutamine Glutaminase (GLS)

41 Channelling potassium to fight cancer Chandy & Norton Nature Sept 2016

42 Take home messages Effector CD8 T cells are the key agents of adaptive immune responses to cancer These cells integrate a multitude of signals and adapt their functional output (cytolysis, cytokines) Rather than exhaustion, functional adaptation Metabolic shifts regulate T cell differentiation and anti-tumor activity Metabolites in the TME matter!

43 Therapy of cancer standard of SURGERY care CHEMOTHERAPY RADIOTHERAPY IMMUNOTHERAPY

44 Thank you