Abstract IA30: 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 is now a 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%. A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late-stage melanoma patients. Altogether, the FDA has approved 17 checkpoint antibodies/indications for melanoma and lung cancer. Emerging data suggest that 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, it is becoming clear that certain types of tumors with lower burdens of mutations (e.g., prostate, breast, and kidney cancer) present special challenges for immune therapy. Strategies for effective treatment of such tumors will be discussed. We have also used high-parameter flow cytometry to identify the cellular mechanisms of CTLA-4 and PD-1 blockade. These are mostly nonoverlapping, which may be a partial explanation for the enhanced effect of the combination. 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; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA30.