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Reprogramming T cell metabolism with a click
Cancer therapies in which tumor-specific T cells are transferred into a patient often fail to control solid tumors. This is partially due to metabolic dysfunction of the transferred T cells at the tumor site. In this study, Hao et al. reprogrammed T cells by anchoring, and clicking, a drug that modulates metabolism to the surface of the T cells. This drug, avasimibe, increased cholesterol in the T cell membrane, which enhanced T cell activation, promoted tumor cell killing, and extended survival in mouse models of melanoma and glioblastoma. Thus, using click chemistry to anchor drugs on the surface of T cells may be a useful technique to improve functionality of adoptive T cell therapies.
Abstract
Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.
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