Cancer immunity and immunotherapy. General principles

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1 1 Cancer immunity and immunotherapy Abul K. Abbas UCSF General principles 2 The immune system recognizes and reacts against cancers The immune response against tumors is often dominated by regulation or tolerance Evasion of host immunity is one of the hallmarks of cancer Some immune responses promote cancer growth Immunotherapies have revolutionized the care of cancer patients Converting a lethal disease to a chronic one 1

2 T cell responses to tumors 3 Cross-presentation of tumor antigens 4 2

3 Immune phenotypes that predict better survival 5 Analysis of 124 published articles on correlation of T cell subsets and prognosis of 20 cancer types Fridman et al. Nat Rev Cancer 12:298, 2012 Types of tumor antigens 6 Types of T Tumor Antigens Examples Neoantigens generated by mutations unrelated to tumorigenesis Random passenger mutations in common cancers Protein antigens expressed by an oncogenic virus EBV nuclear antigens in EBV+ lymphomas Aberrantly expressed normal proteins Cancer testis antigens in many tumors Overexpressed normal proteins HER2/neu in breast cancers 3

4 Types of tumor antigens 7 Most tumor antigens that elicit immune responses are neoantigens Not present normally, so no tolerance Produced by mutated genes that may be involved in oncogenesis (driver mutations) or reflect genomic instability (passenger mutations) In tumors caused by oncogenic viruses (HPV, EBV), neoantigens are encoded by viral DNA Some are unmutated proteins (tyrosinase, cancer-testis antigens) Derepressed (epigenetic changes), overexpressed Identification of tumor neoantigens 8 Next gen sequencing and/or RNA-seq Identification of HLAbinding peptides MHC-peptide multimer and/or functional assays Ton N. Schumacher, and Robert D. Schreiber Science 2015;348:

5 Immune responses that promote tumor growth 9 M2 Coussens et al. Science 339:286, 2013 The history of cancer immunotherapy: from empirical approaches to rational, science-based therapies 10 5

6 11 Passive immunotherapy 12 6

7 Antibody therapies Anti-tumor antibodies Variable success (anti-cd20, -Her2) Antibody-drug conjugates Payload is most often a drug that interferes with the cell cycle; limited by toxicities BiTE antibodies (bispecific T cell engagers) In clinical development Adoptive cell therapy Purify T cells (NK cells?) from blood or tumor infiltrate, expand in vitro, transfer into patients Major problem is low frequency of T cells specific for tumor antigens Attempts to overcome the problem by introducing tumor-specific antigen receptor into patient T cells Problems with introducing TCR? Tumors often lose MHC expression 7

8 Development of chimeric antigen receptors 15 V H V L Chimeric antigen receptors 16 Remarkable success in B cell acute leukemia (targeting CD19); up to 90% remission) 8

9 Limitations and challenges of CAR-T cell therapy Cytokine storm many T cells respond to target antigen Requires anti-inflammatory therapy (anti-il-6r) Risk of long-term damage (especially brain) Resistance due to loss of target antigen Simultaneous introduction of two CARs Limitations and challenges of CAR-T cell therapy Cytokine storm many T cells respond to target antigen Resistance due to loss of target antigen T cells acquire inhibitory receptors Phenomenon of exhaustion May be overcome with anti-pd1 antibody or gene editing Not yet successful in solid tumors Problem of T cells entering tumor site Selection of tumor antigen Technical challenges, high cost 9

10 Dendritic cell vaccination 19 Blocking CTLA-4 promotes tumor rejection: CTLA-4 limits immune responses to tumors 20 Administration of antibody that blocks CTLA-4 in tumor-bearing mouse leads to tumor regression 10

11 Checkpoint blockade: Removing the brakes on the immune response 21 Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing immune responses against tumors) Even more impressive results with anti-pd-1 in cancer patients Checkpoint blockade for cancer immunotherapy Checkpoint blockade Effector phase Priming phase 11

12 23 Why do tumors engage CTLA-4 and PD-1? CTLA-4: tumor induces low levels of B7 costimulation preferential engagement of the high-affinity receptor CTLA-4 PD-1: tumors may express PD-L1 Remains incompletely understood These mechanisms do not easily account for all tumors 24 Is checkpoint blockade more effective than vaccination for tumor therapy? Tumor vaccines have been tried for many years with limited success Immune evasion is a hallmark of cancer Multiple regulatory mechanisms Vaccines have to overcome regulation Tumor vaccines are the only examples of therapeutic (not prophylactic) vaccines Vaccination after tumor detection means regulatory mechanisms are already active 12

13 25 Adverse effects of checkpoint blockade Inevitable consequence of blocking essential mechanisms of self-tolerance: Adverse effects of checkpoint blockade 26 Inevitable consequence of blocking essential mechanisms of self-tolerance: Autoimmune reactions Unusual phenotypes: Brittle diabetes with anti-pd1 Anterior pituitary lesions with anti-ctla4 Myocarditis with combination Others commonly seen: colitis, exacerbated arthritis 13

14 Response to checkpoint blockade Gay and Prasad 2017 Biomarkers for successful checkpoint blockade therapy Nature of tumor infiltrate Frequency of T cells with phenotype of exhaustion (high expression of PD1, CTLA4) Frequency of tumor antigen-specific T cells (will require assays for antigen specificity) 14

15 Biomarkers for successful checkpoint blockade therapy Nature of tumor infiltrate PDL1 expression On tumor cells or DCs Mutational burden in tumor Source of neoatigens Anti-PD1 approved for all recurrent tumors with mismatch repair (genomic instability) Composition of microbiome? Unexplained E.g. liver vs lung mets in melanoma Combination strategies for cancer immunotherapy 30 Combinations of checkpoint blockers: multiple or bispecific antibodies targeting two checkpoints Already done with CTLA-4 and PD-1 Many others being tried (rationale?) 15

16 T cell activating and inhibitory receptors 31 Inhibitory receptors CTLA-4 PD-1 TIM-3 Activating receptors (costimulators) CD28 ICOS OX40 T cell TCR TIGIT LAG-3 BTLA CD27 GITR CD137 (4-1BB) Combination strategies for cancer immunotherapy 32 Combinations of checkpoint blockers: multiple or bispecific antibodies targeting two checkpoints Checkpoint blockade (anti-pd1) + Block other inhibitory pathways (IDO, Tregs) Vaccination (e.g. DCs presenting tumor antigen) Immune stimulator (agonist against activating receptor, innate immune stimulus, cytokine e.g. IL-2) Radiation, chemotherapy or targeted kinase inhibitor 16