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Genetic drivers of CAR T-cell persistence and function using in vivo CRISPR screens

Knudsen NH, Escobar G, Korell F, et al. In Vivo CRISPR Screens Identify Modifiers of CAR T Cell Function in Myeloma. Nature. 2025; (doi: 10.1038/s41586-025-09489-8).

Scientists employed in vivo screening to identify genes that affect chimeric antigen receptor (CAR) T-cell persistence and function — findings that could inform efforts to improve treatment efficacy. Initially successful CAR-T interventions are often undermined by relapse driven by progressive loss of CAR-T cells. Using a human model of multiple myeloma, researchers performed loss-of-function CRISPR screens in anti-BCMA CAR T cells. By tracking CRISPR library-edited T cells at early and later intervals of time, and in both in vivo and in vitro environments, they found that context is an important influence on cell expansion and persistence. Chief among the observed associations, investigators noted cyclin-dependent kinase inhibitor 1B (encoded by CDKN1B) for its inhibitory effect on CAR T-cell fitness at later time points in vivo. CDKN1B ablation improved CAR T-cell performance, enhancing proliferation and effector function to the extent that tumor clearance and overall survival were significantly increased. The work showcases the potential of in vivo screening for identifying genes that promise to enhance CAR T-cell efficacy, the study authors conclude.

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