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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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Zheng, Y. Y., Wang, X., & Huang, M. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0040 · Cited by 19
Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia
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The Interplay between Dysregulated Metabolism and Epigenetics in Cancer
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Immunological Aspects of Cancer Cell Metabolism
Ucche, S., & Hayakawa, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105288 · Cited by 17
“The combination of CB-839 with immune checkpoint blockade increased IFN-γ -associated T cell inflammatory gene expression [68].”
BackgroundTargeting glutamine metabolism crosstalk with tumor immune response
Dong, C., Zhao, Y., Han, Y., Li, M., & Wang, G. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189257 · Cited by 21
Impact of NSCLC metabolic remodeling on immunotherapy effectiveness
Lv, L., Huang, R. H., Li, J., Xu, J., & Gao, W. (2022) · Biomarker Research · doi:10.1186/s40364-022-00412-1 · Cited by 16
Glutamine metabolism and radiosensitivity: Beyond the Warburg effect
Alden, R. S., Kamran, M. Z., Bashjawish, B., & Simone, B. A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1070514 · Cited by 18
“demonstrated that in effector T-cell populations with transient GLS deficiency, IL2 promotes Th1 phenotype and CD8 T-cell function, suggesting that inhibition of glutamine metabolism enhances an anti-tumor immune composition (24, 50).”
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Zhu, J., Shen, K., Su, Q., Yao, G., & Chen, X. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1662464 · Cited by 13
Oxidative Stress in the Tumor Immune Microenvironment: Mechanisms and Therapeutic Perspectives
Wang, Z., Li, B., Tang, P., Yan, F., Wang, S., Leng, G., Dawa, P., Chen, Y., Guo, Y., Yang, P., et al. (2026) · MedComm – Oncology · doi:10.1002/mog2.70068 · Cited by 14
Review to Understand the Crosstalk between Immunotherapy and Tumor Metabolism
Pandey, P., Khan, F., Upadhyay, T. K., & Maqsood, R. (2023) · Molecules · doi:10.3390/molecules28020862 · Cited by 13
“Finally, CB-839 increases the infiltration of effector T cells in tumors and amplifies the anti-tumor effects of these checkpoint inhibitors in mice melanoma models with high mutation burden tumors [84].”
BackgroundZhang, H., Xu, W., Zhu, H., Chen, X., & Tsai, H. (2024) · Journal of Cancer · doi:10.7150/jca.92502 · Cited by 13
“Preclinical studies using murine melanoma models, anti-PD1 or anti-CTLA4 with glutaminase inhibitors, and other metabolic modulators have demonstrated that modulating the metabolism can increase the efficacy of PD-1/PD-L1 therapy[181].”
BackgroundYang, R., Guo, Z., Zhao, Y., Ma, L., Li, B., & Yang, C. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00590-1 · Cited by 12
Choi, S. Y. C., Ribeiro, C. F., Wang, Y. Z., Loda, M. F., Plymate, S. R., & Uo, T. (2022) · Biomolecules · doi:10.3390/biom12111590 · Cited by 13
Metabolism in the tumor microenvironment: implications for pathogenesis and therapeutics
Wik, J. A., Berge, E. R., Stromsnes, K., & Skålhegg, B. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1610255 · Cited by 13
Kang, H. W., Kim, J. H., Jeong, J. W., Fang, S., Yun, W., Hye-Sol, J. U. N. G., Kwon, W., Jang, J. S., Kim, H. J., & Park, J. S. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01596-w · Cited by 13
“Targeting SLC6A14, either alone or in combination with glutamine metabolism inhibitors and ICB therapy, may offer a promising strategy to improve treatment outcomes in glutamine-dependent pancreatic cancer.”
InfluentialMetabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy
Masci, D., Puxeddu, M., Silvestri, R., & Regina, G. L. (2024) · Molecules · doi:10.3390/molecules29092110 · Cited by 11
“Furthermore, in combination with anti-PD1 or anti-CTLA4 antibodies, it synergized their activity [154].”
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Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents
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Enzymatic depletion of circulating glutamine is immunosuppressive in cancers
Kumar, M., Leekha, A., Nandy, S., Kulkarni, R. S., Martinez-Paniagua, M. A., Sefat, K. M. S. R., Willson, R. C., & Varadarajan, N. (2024) · iScience · doi:10.1016/j.isci.2024.109817 · Cited by 10
“16,17,22,23 26 A fundamental question that needs to be answered is what is the integrated impact of inhibiting glutamine metabolism of both the cancer cells and the immune system?”
BackgroundAmmonia metabolism and ammonia-induced cell death: role in cancer therapy
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“Currently, Preclinical studies have demonstrated significant anti-tumor activity across diverse tumor models, with ongoing clinical trials (e.g., NCT02071862, NCT03428028) evaluating its safety and efficacy in renal cell carcinoma, triple-negative breast cancer, and other malignancies [83–87].”
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Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance
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The Landscape of Cancer Metabolism as a Therapeutic Target
Ohshima, K. (2025) · Pathology International · doi:10.1111/pin.70034 · Cited by 11
“In melanoma, treatment with CB ‐ 839 in combination with anti ‐ programmed death 1 (anti ‐ PD1) or anti ‐ CTLA4 antibodies increased CD8 + T ‐ cell infiltration into tumors, enhancing the antitumor response [19].”
Kakish, H. H., Ahmed, F. A., Elshami, M., Loftus, A. W., Hoehn, R. S., Ammori, J. B., Ocuin, L. M., Winter, J. M., Bordeaux, J. S., Mangla, A., et al. (2022) · Cancers · doi:10.3390/cancers14215184 · Cited by 9
Endothelial metabolic zonation in the vascular network: a spatiotemporal blueprint for angiogenesis
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Targeting Metabolic Reprogramming in Tumor: From Mechanisms to Precision Immunotherapies
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“23 Despite these advances, how mitochondrial glutamine metabolism influences PDAC liver metastasis and the molecular mechanisms governing the antitumour immune response following changes in glutamine availability in the metastatic organ remains to be elucidated.”
Metabolic Profiling to Assess Response to Targeted and Immune Therapy in Melanoma
Farah, C., Mignion, L., & Jordan, B. F. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031725 · Cited by 8
“For instance, one ongoing clinical trial is currently testing the combination of CB-839 (glutaminase inhibitor) with the immune checkpoint inhibitor nivolumab in melanoma patients [107,108].”
BackgroundCB-839 induces reversible dormancy in lung tumor-cells
Jamshidi‐Parsian, A., Jenkins, S. V., Tran, A., Bragg, A., Davis, R., Griffin, C., Siegel, E. R., Dings, R. P. M., Griffin, R. J., & Boysen, G. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176912 · Cited by 8
Benito-Lopez, J. J., Marroquin-Muciño, M., Perez-Medina, M., Chavez-Dominguez, R., Aguilar‐Cázares, D., Galicia-Velasco, M., & López-González, J. S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1101503 · Cited by 7
A hormetic response model for glutamine stress in cancer
Grenier, S. F., & Commisso, C. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.008 · Cited by 7
Macropinocytosis: Both a Target and a Tool for Cancer Therapy
Zhao, M., Zhou, L., Zhai, Y., Sun, A., Shao, G., & Lin, Q. (2025) · Biomolecules · doi:10.3390/biom15070936 · Cited by 8
“…glutaminase inhibitor (GLSi) with a favorable systemic tolerance, has been observed to significantly reduce the glutamine to α -ketoglutarate ( α -KG) conversion in tumor cells while concomitantly enhancing the activity of T cell-mediated immunotherapy in the context of combating melanoma [59].”
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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