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CRISPR engineering of armored CAR T cells enables tumor-restricted payload delivery with enhanced safety and efficacy

ABSTRACT: CRISPR engineering of armored CAR T cells enables tumor-restricted payload delivery with enhanced safety and efficacy

PROVIDER: PRJNA1241771 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR32856203.fastq.gz	Fastqsanger.gz
	SRR32856205.fastq.gz	Fastqsanger.gz
	SRR32856207.fastq.gz	Fastqsanger.gz

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CRISPR engineering of armored CAR T cells enables tumor-restricted payload delivery with enhanced safety and efficacy

Project description:The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid tumors is limited by immunosuppression and antigen heterogeneity. To overcome these barriers, “armored” CAR T cells, which secrete proinflammatory cytokines, have been developed. However, their clinical application has been limited due to toxicities related to peripheral expression of the armoring transgene. Here, we developed a CRISPR knock-in strategy that leverages the regulatory mechanisms of endogenous genes to drive transgene expression in a tumor-localized manner. By screening endogenous genes with tumor-restricted expression, the NR4A2 and RGS16 promoters were identified to support the delivery of cytokines such as IL-12 and IL-2 directly to the tumor site, leading to enhanced anti-tumor efficacy and long-term survival of mice in both syngeneic and xenogeneic models. This was concomitant with improved CAR T cell polyfunctionality, activation of endogenous anti-tumor immunity, a favorable safety profile, and was applicable using CAR T cells from patients.

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