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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.

2025-06-18 | GSE292859 | GEO

Gene expression from armored CAR T cell

Project description:Compare the gene expression profile among armored IL-18 secreting CAR T cells and second-generation CAR T cells

2017-04-03 | GSE97343 | GEO

Gene expression from armored CAR T cell and TAMs

Project description:Compare the gene expression profile among armored IL-12 secreting CAR T cells and second-generation CAR T cells and TAMs recovered from both groups

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Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment.

Project description:Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs.

| S-EPMC8657158 | biostudies-literature

PrePhage safety

Project description:PrePhage safety

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IL-36γ Armored CAR T Cells Reprogram Neutrophils to Induce Endogenous Antitumor Immunity

Project description:Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors due to obstacles of antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Previous efforts focused on enhancing cytotoxicity and persistence of CAR T cells, while the feasibility of improving their therapeutic efficacy by leveraging the modulatory effects of CAR T cells on host anti-tumor immunity remains unclear. Here, we report that IL-36γ armored CAR T cells eradicated primary solid tumors and enabled rejection of rechallenged antigen-negative tumors. IL-36γ armored CAR T cells favorably modulated the TME and reprogrammed unique neutrophil subsets with tumoricidal ability and antigen-(cross)presenting functions, resulting in the induction of endogenous T cells recognizing tumor antigens beyond CAR-targeted antigens. Our study demonstrates that neutrophil engagement by CAR T cells is a critical step in the establishment of the cancer-immunity cycle and introduces a broadly applicable method to overcome key barriers to adoptive cell therapies for solid tumors.

2025-12-31 | GSE306905 | GEO

AgRP neurons shape the sperm small RNA payload

Project description:AgRP neurons shape the sperm small RNA payload

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fate-restricted HSCs

Project description:fate-restricted HSCs

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Transcription profiling of brain tissue from mice after safety or fear conditioning

Project description:safety versus fear conditioning. Mice were trained with 4 unpaired (Safety) or paired (Fear) CS-US presentations over 3 days. Mice were killed by decapitation 4hrs after the last training session.

2008-11-28 | E-MEXP-1358 | biostudies-arrayexpress

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