Abstract: Series 114, Lecture 5
The Harvey Lectures Series 114 (2018—2019)
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Lecture #5: Thursday, March 21, 2019 — Watch Video of Lecture
Immune Checkpoint Blockade in Cancer Therapy: New Insights and Opportunities, and Prospects for Cures
James P Allison, PhD
Chair of the Department of Immunology
Vivian L Smith Distinguished Chair in Immunology
Director of the Parker Institute for Cancer Research
Executive Director of the Immunotherapy Platform
MD Anderson Cancer Center
Houston, Texas
The non-redundant mechanisms that limit T cell responses offer strategies for mobilizing the cancer immune response. CTLA-4, the best characterized immune checkpoint, inhibits T cell proliferation by blocking the interaction of the costimulatory molecule CD28 with its ligands on dendritic cells. Ipilimumab, an anti-CTLA-4 antibody, has been effective against multiple tumor types in pre-clinical and clinical studies, and provides long term survival to ~20% of late stage melanoma patients. PD-1, another checkpoint, seems to inhibit T cell antigen receptor mediated signaling. Many tumor cells express PD-L1, the PD-1 ligand. Antibodies to PD-1or PD-L1 provided objective responses against several tumor types in clinical trials in about 25% of patients. Combined anti-PD-1 and anti-CTLA-4 provided objective responses in ~50% of late stage melanoma patients. We used high parameter flow cytometry to identify the mostly non-overlapping cellular mechanisms of CTLA-4 and PD-1 blockade, which may partially explain the enhanced effect of their combination. T cell responses to tumor cells appear directed toward neoantigens arising from carcinogenesis-related mutational events. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, tumors with lower mutational burdens (prostate, breast, and kidney cancer) present challenges. Strategies for their treatment will be discussed.