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Annual Review of Chemical and Biomolecular Engineering

Volume 13, 2022

Engineering Next-Generation CAR-T Cells: Overcoming Tumor Hypoxia and Metabolism

Abstract

T cells engineered to express chimeric antigen receptors (CARs) have shown remarkable success in treating B-cell malignancies, reflected by multiple US Food and Drug Administration–approved CAR-T cell products currently on the market. However, various obstacles have thus far limited the use of approved products and constrained the efficacy of CAR-T cell therapy against solid tumors. Overcoming these obstacles will necessitate multidimensional CAR-T cell engineering approaches and better understanding of the intricate tumor microenvironment (TME). Key challenges include treatment-related toxicity, antigen escape and heterogeneity, and the highly immunosuppressive profile of the TME. Notably, the hypoxic and nutrient-deprived nature of the TME severely attenuates CAR-T cell fitness and efficacy, highlighting the need for more sophisticated engineering strategies. In this review, we examine recent advances in protein- and cell-engineering strategies to improve CAR-T cell safety and efficacy, with an emphasis on overcoming immunosuppression induced by tumor metabolism and hypoxia.

Keyword(s): adoptive cell therapy, CAR-T cell, chimeric antigen receptor, genetic engineering, hypoxia, metabolism
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/content/journals/10.1146/annurev-chembioeng-092120-092914
2022-06-07
2024-04-20
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Engineering Next-Generation CAR-T Cells: Overcoming Tumor Hypoxia and Metabolism
Annual Review of Chemical and Biomolecular Engineering 13, 193 (2022); https://doi.org/10.1146/annurev-chembioeng-092120-092914
/content/journals/10.1146/annurev-chembioeng-092120-092914
/content/journals/10.1146/annurev-chembioeng-092120-092914
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