TY - JOUR
T1 - The glutaminase inhibitor CB-839 (Telaglenastat) enhances the antimelanoma activity of T-cell-mediated immunotherapies
AU - Varghese, Sruthy
AU - Pramanik, Snigdha
AU - Williams, Leila J.
AU - Hodges, Hannah R.
AU - Hudgens, Courtney W.
AU - Fischer, Grant M.
AU - Luo, Catherine K.
AU - Knighton, Barbara
AU - Tan, Lin
AU - Lorenzi, Philip L.
AU - Mackinnon, Andrew L.
AU - McQuade, Jennifer L.
AU - Hailemichael, Yared
AU - Roszik, Jason
AU - Peng, Weiyi
AU - Gopal, Y. N.Vashisht
N1 - Funding Information:
Y.N. Vashisht Gopal was supported by a research grant from Calithera Biosciences (55350) and a research grant from the Melanoma Research Alliance (348483). The Metabolomics Core Facility at MDACC is supported by Cancer Prevention and Research Institute of Texas grant RP130397, NIH grants S10OD012304-01, U01CA235510, and P30CA016672. The authors would like to thank Dr. Michael Davies for providing laboratory resources, advice, and critical review of the study, Chantale Bernatchez and the MDACC melanoma moonshot program for patient cell lines and adoptive TILs, Rishika Prasad and Renato Guerrieri for technical assistance, Marina Gelman (Calithera Biosciences) for scientific expertise and advice, Funda Meric-Bernstam and Hussein Tawbi for discussions leading to the development of this study.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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 (aKGA) 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 burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNg)-associated gene expression in the tumors. Together, these results provide a strong rationale for combining CB-839 with immune therapies to improve efficacy of these treatments against melanoma.
AB - 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 (aKGA) 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 burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNg)-associated gene expression in the tumors. Together, these results provide a strong rationale for combining CB-839 with immune therapies to improve efficacy of these treatments against melanoma.
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U2 - 10.1158/1535-7163.MCT-20-0430
DO - 10.1158/1535-7163.MCT-20-0430
M3 - Article
C2 - 33361272
AN - SCOPUS:85101171306
SN - 1535-7163
VL - 20
SP - 500
EP - 511
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 3
ER -