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Targeting oncometabolism to maximize immunotherapy in malignant brain tumors

Abstract

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed “tumor immunometabolism”. Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

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Fig. 1: Metabolic interaction(s) between glioma cells, T cells, and myeloid-derived suppressor cells (MDSCs).
Fig. 2: Targeting tumor metabolism in gliomas with biologics and small-molecule inhibitors.

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Acknowledgements

GKF is supported by grants from the U.S. Food and Drug Administration (R01FD005379 and R01FD006368), the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, Andrew McDonough B+ Foundation, and Cannonball Kids’ cancer Foundation. LP-J has been supported by a senior research fellowship FISM—Fondazione Italiana Sclerosi Multipla—cod. 2017/B/5 and financed or co financed with the “5 per mille” public funding, a Wellcome Trust CRCD Fellowship (RG G105713), and the Addenbrooke’s Charitable Trust (RG 97519). EMT is supported by the Department of Defense (CA171067), The Musella Foundation for Brain Tumor Research and Information, and the Pediatric Brain Tumor Foundation. We thank Adam A. Dmytriw for reviewing the manuscript.

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Correspondence to Joshua D. Bernstock or Gregory K. Friedman.

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JDB has an equity position in Treovir LLC, an oHSV clinical stage company and is a member of the POCKiT Diagnostics Board of Scientific Advisors. The remaining authors declared that no conflict of interest exists.

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Bernstock, J.D., Kang, KD., Klinger, N.V. et al. Targeting oncometabolism to maximize immunotherapy in malignant brain tumors. Oncogene 41, 2663–2671 (2022). https://doi.org/10.1038/s41388-022-02312-y

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