The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell–Mediated Immunotherapies

作者：Sruthy Varghese, Snigdha Pramanik, Leila J. Williams, Hannah R. Hodges, Courtney W. Hudgens, Grant M. Fischer, Catherine K. Luo, Barbara G. Knighton, Lin Tan, Philip L. Lorenzi, Andrew L. MacKinnon, Jennifer Leigh McQuade, Yared Hailemichael, Jason Roszik, Weiyi Peng, Y.N. Vashisht Gopal · 发表于：Molecular Cancer Therapeutics · 年份：2020 · DOI：10.1158/1535-7163.mct-20-0430 · 被引用次数：176 · 研究领域：Cancer, Hypoxia, and Metabolism、Cancer Immunotherapy and Biomarkers、Cancer Research and Treatments

Abstract Immune-checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of patients with melanoma. However, a majority of patients do not respond to these agents, and many responders experience disease relapse. Although numerous innovative treatments are being explored to offset the limitations of these agents, novel therapeutic combinations with immunotherapies have the potential to improve patient responses. In this study, we evaluated the antimelanoma activity of immunotherapy combinations with Telaglenastat (CB-839), a potent glutaminase inhibitor (GLSi) that has favorable systemic tolerance. In in vitro TIL:tumor coculture studies, CB-839 treatment improved the cytotoxic activity of autologous TILs on patient-derived melanoma cells. CB-839 treatment decreased the conversion of glutamine to alpha-ketoglutarate (αKGA) more potently in tumor cells versus TILs in these cocultures. These results suggest that CB-839 may improve immune function in a tumor microenvironment by differentially altering tumor and immune cell metabolism. In vivo CB-839 treatment activated melanoma antigen–specific T cells and improved their tumor killing activity in an immune-competent mouse model of adoptive T-cell therapy. Additionally, the combination of CB-839 with anti-PD1 or anti-CTLA4 antibodies increased tumor infiltration by effector T cells and improved the antitumor activity of these checkpoint inhibitors in a high mutation bur...