Abstract
CRISPR technologies have begun to revolutionize Tcell therapies; however, conventional CRISPR-Cas9 genome-editing tools are limited in their safety, efficacy, and scope. To address these challenges, we developed multiplexed effector guide arrays (MEGA), a platform for programmable and scalable regulation of the Tcell transcriptome using the RNA-guided, RNA-targeting activity of CRISPR-Cas13d. MEGA enables quantitative, reversible, and massively multiplexed gene knockdown in primary human Tcells without targeting or cutting genomic DNA. Applying MEGA to a model of CAR Tcell exhaustion, we robustly suppressed inhibitory receptor upregulation and uncovered paired regulators of Tcell function through combinatorial CRISPR screening. We additionally implemented druggable regulation of MEGA to control CAR activation in a receptor-independent manner. Lastly, MEGA enabled multiplexed disruption of immunoregulatory metabolic pathwaysto enhance CAR Tcell fitness and anti-tumor activity invitro and invivo. MEGA offers a versatile synthetic toolkit for applications in cancer immunotherapy and beyond.
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