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The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell–Mediated Immunotherapies
Open accessPublished version of a preprint
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 burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNγ)–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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“Besides, other metabolic modulators such as glutaminase inhibitor also had a synergistic effect with α-PD-1/PD-L1 in murine tumor models [338].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [338]
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“That said, telaglenastat has also been shown to synergize with CTLA4 and PD1 blockers in immunocompetent models of melanoma 126 , which suggests that this agent does mediate therapeutically relevant immunostimulatory effects.”
Metadata
- Authors
- Varghese, S., Pramanik, S., Williams, L. J., Hodges, H. R., Hudgens, C. W., Fischer, G. M., Luo, C. K., Knighton, B., Tan, L., Lorenzi, P. L., Mackinnon, A. L., McQuade, J. L., Hailemichael, Y., Roszik, J., Peng, W., & Vashisht Gopal, Y. N.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Calithera (United States) (US)
- University of Houston (US)
- 1Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2021-03-01
- Volume
- 20
- Issue
- 3
- Pages
- 500-511
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC7933078
- OpenAlex
- W3116829754
- Cited by
- 171
- References
- 35
- Citations by year
- 2026: 31 · 2025: 50 · 2024: 36 · 2023: 17 · 2022: 26 · 2021: 11
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Melanoma Research Alliance (348483)
- Calithera Biosciences (55350)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CB-839, telaglenastat, glutaminase inhibitors, melanoma, adoptive T cell therapy, tumor-infiltrating lymphocytes, immune checkpoint inhibitors, anti-PD-1, anti-CTLA-4, alpha-ketoglutarate, cancer metabolism, interferon-gamma, tumor microenvironment, combination immunotherapy
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Glutaminase, Humans, Immunotherapy, Melanoma, T-Lymphocytes, Mice, Tumor Microenvironment
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