Abstract IA20: Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures

Abstract

Abstract The existence of multiple nonredundant inhibitory pathways that limit T-cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T-cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen-presenting cells. Antibodies to CTLA-4 have proved effective against multiple tumor types in both preclinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long-term (>4 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late-stage melanoma. In 2011 it was approved by the FDA for treatment of late-stage melanoma, and it remains part of the standard of care for that disease. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T-cell antigen receptor-mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. Combination of anti-PD-1 and anti-CTLA-4 in melanoma provides objective responses in about 50% of late-stage melanoma patients. The FDA has now approved 6 different checkpoint antibodies for a variety of cancers including urothelial, renal, and lung cancers. A major focus of current efforts is the rational identification of combinatorial treatments that improve the response rate and expand the range of immune checkpoint inhibitors. We used high-parameter flow cytometry to identify the mostly nonoverlapping cellular mechanisms of CTLA-4 and PD-1 blockade, which may partially explain the enhanced effect of their combination. Further work has shown that combined CTLA-4 and PD-1 blockade, which provides higher response rates against a wider range of cancers than either monotherapy, acts through a population of T cells not enriched in either single treatment. T-cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, tumors with lower burdens of mutations (e.g., prostate, breast, and kidney cancer) present special challenges for immune therapy. Recent evidence suggests that even the few neoantigens carried by these can provide targets for immune attack. Strategies for effective treatment of such tumors will be discussed. Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA20.