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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2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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T cell responses to tumors 3

Cross-presentation of tumor antigens 4

2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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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2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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Coussens et al. Science 339:286, 2013

M2

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

2018 Advanced Course in Basic & Clinical Immunology

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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

2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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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2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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

2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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

2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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

2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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

2018 Advanced Course in Basic & Clinical Immunology

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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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2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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)

2018 Advanced Course in Basic & Clinical Immunology

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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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2018 Advanced Course in Basic & Clinical Immunology

February 20, 2018

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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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