Cancer immunity and immunotherapy · 2018-04-03 · 2018 Advanced Course in Basic & Clinical...
Transcript of Cancer immunity and immunotherapy · 2018-04-03 · 2018 Advanced Course in Basic & Clinical...
2018 Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Cancer immunity and immunotherapyAbul K. Abbas
UCSF
General principles
• 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
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T cell responses to tumors 3
Cross-presentation of tumor antigens 4
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Fridman et al. Nat Rev Cancer 12:298, 2012
Immune phenotypes that predict better survival
Analysis of 124 published articles on correlation of T cell subsets and prognosis of 20 cancer types
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Types of tumor antigens
Random passenger mutations in
common cancers
EBV nuclear antigensin EBV+ lymphomas
Cancer testis antigens in many
tumors
HER2/neu in breast cancers
Aberrantly expressed normal proteins
Overexpressed normal proteins
Protein antigens expressed by an oncogenic virus
Neoantigens generated by
mutations unrelated to tumorigenesis
ExamplesTypes of T Tumor Antigens
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• 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), over-
expressed
Types of tumor antigens 7
Ton N. Schumacher, and Robert D. Schreiber Science 2015;348:69-74
Identification of tumor neoantigens
Next gen sequencing and/or RNA-seq
Identification of HLA-binding peptides
MHC-peptide multimerand/or functional assays
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Coussens et al. Science 339:286, 2013
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Immune responses that promote tumor growth 9
The history of cancer immunotherapy: from empirical approaches to rational, science-based therapies
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Passive immunotherapy12
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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
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Development of chimeric antigen receptors
VH VL
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Chimeric antigen receptors
Remarkable success in B cell acute leukemia (targeting CD19); up to 90% remission)
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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
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Dendritic cell vaccination19
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Blocking CTLA-4 promotes tumor rejection: CTLA-4 limits immune responses to tumors
Administration of antibody that blocks CTLA-4 in tumor-bearing mouse leads to tumor regression
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Checkpoint blockade: Removing the brakes on the immune response
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
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Checkpoint blockade
Prim
ing
phas
e Ef
fect
or p
hase
Checkpoint blockade for cancer immunotherapy
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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
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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
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Adverse effects of checkpoint blockade
• Inevitable consequence of blocking essential mechanisms of self-tolerance:
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Adverse effects of checkpoint blockade
• 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
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Gay and Prasad 2017
Response to checkpoint blockade
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)
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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
• Combinations of checkpoint blockers: multiple or bispecific antibodies targeting two checkpoints • Already done with CTLA-4 and PD-1• Many others being tried (rationale?)
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T cell TCR
CD28
ICOS
OX40
GITR
CD137 (4-1BB)
CD27
Activating receptors (costimulators)
Inhibitory receptors
CTLA-4
PD-1
TIM-3
TIGIT
LAG-3
BTLA
T cell activating and inhibitory receptors
Combination strategies for cancer immunotherapy
• Combinations of checkpoint blockers: multiple or bispecificantibodies 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
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