abul k. abbas ucsf - ufba...abul k. abbas ucsf. t cell responses to tumors 2. 3. passive...
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Cancer immunotherapy
Abul K. AbbasUCSF
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T cell responses to tumors 2
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Passive immunotherapy4
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Tumor-specific T cell therapy
• Problem with initial approaches: not enough tumor-specific T cells
• How to generate large numbers? – Transfect tumor-specific antigen receptor into
T cells, expand the cells in vitro
• Which tumor-specific antigen receptor to express in T cells? – Problems with expressing TCR
– Alternative: chimeric antigen receptors
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Development of chimeric antigen receptors
VH VL
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Chimeric antigen receptor-T cell (CAR-T) therapy
• Remarkable success in B cell acute leukemia (targeting CD19); up to 90% complete remission
• Risk of cytokine storm
• Outgrowth of antigen-loss variants of tumors?
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Limitations and challenges of CAR-T cell therapy
• Cytokine release syndrome – many T cells respond to target antigen
• Not yet effective against solid tumors
• Resistance due to loss of target antigen
• Technically challenging and expensive
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Immune checkpoints
• Inhibitory receptors on T cells (“coinhibitors”) block activation
• CTLA-4: competes with CD28, reduces costimulation
• PD-1: activates phosphatase, blocks kinase-dependent signals from CD28 and TCR
• Many others described
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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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Risks of blocking CTLA-4 or PD-1
• Blocking a mechanism of self-tolerance leads to:
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Risks of blocking CTLA-4 or PD-1
• Blocking a mechanism of self-tolerance leads to:
• Autoimmune reactions – Immune related adverse events
– Severity of adverse events has to be balanced against potential for treating serious cancers
– More severe with anti-CTLA4 than with anti-PD1 antibody
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What types of tumors respond best to checkpoint blockade therapy
• Many mutations in tumor (mutations produce neoantigens that are recognized by T cells)
• Tumor infiltrate contains many T cells with high expression of PD-1, CTLA-4
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