Dataset Information

CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts.

ABSTRACT: One reason underlying the failure of current chimeric antigen receptor (CAR) immune therapy to treat solid tumors adequately is insufficient tumor infiltration of CAR immune cells. To address the issue, we electroporated natural killer (NK) cells with two mRNA constructs encoding the chemokine receptor CXCR1 and a CAR targeting tumor-associated NKG2D ligands. The CXCR1-modified NK cells displayed increased migration toward tumor supernatants in vitro and augmented infiltration into human tumors in vivo in subcutaneous and intraperitoneal xenograft models. Most importantly, the cytotoxicity of the CAR-NK cells was not affected by CXCR1 transgene expression, and the enhanced tumor trafficking following intravenous injection resulted in significantly increased antitumor responses in mice carrying established peritoneal ovarian cancer xenografts. Collectively, our findings suggest that the coexpression of CXCR1 and a CAR may provide a novel strategy to enhance therapeutic efficacy of NK cells against solid cancers.

SUBMITTER: Ng YY

PROVIDER: S-EPMC6965500 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts.

Ng Yu Yang YY Tay Johan C K JCK Wang Shu S

Molecular therapy oncolytics 20191224

One reason underlying the failure of current chimeric antigen receptor (CAR) immune therapy to treat solid tumors adequately is insufficient tumor infiltration of CAR immune cells. To address the issue, we electroporated natural killer (NK) cells with two mRNA constructs encoding the chemokine receptor CXCR1 and a CAR targeting tumor-associated NKG2D ligands. The CXCR1-modified NK cells displayed increased migration toward tumor supernatants <i>in vitro</i> and augmented infiltration into human ...[more]

PMID: 31970285

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Project description:Chimeric antigen receptor (CAR) T and CAR NK cell therapies opened new avenues for cancer treatment. Although original successes of CAR T and CAR NK cells for the treatment of hematological malignancies were extraordinary, several obstacles have since been revealed, in particular their use for the treatment of solid cancers. The tumor microenvironment (TME) is competing for nutrients with T and NK cells and their CAR-expressing counterparts, paralyzing their metabolic effective and active states. Consequently, this can lead to alterations in their anti-tumoral capacity and persistence in vivo. High glucose uptake and the depletion of key amino acids by the TME can deprive T and NK cells of energy and building blocks, which turns them into a state of anergy, where they are unable to exert cytotoxic activity against cancer cells. This is especially true in the context of an immune-suppressive TME. In order to re-invigorate the T, NK, CAR T and CAR NK cell-mediated antitumor response, the field is now attempting to understand how metabolic pathways might change T and NK responses and functions, as well as those from their CAR-expressing partners. This revealed ways to metabolically rewire these cells by using metabolic enhancers or optimizing pre-infusion in vitro cultures of these cells. Importantly, next-generation CAR T and CAR NK products might include in the future the necessary metabolic requirements by improving their design, manufacturing process and other parameters. This will allow the overcoming of current limitations due to their interaction with the suppressive TME. In a clinical setting, this might improve their anti-cancer effector activity in synergy with immunotherapies. In this review, we discuss how the tumor cells and TME interfere with T and NK cell metabolic requirements. This may potentially lead to therapeutic approaches that enhance the metabolic fitness of CAR T and CAR NK cells, with the objective to improve their anti-cancer capacity.

Dataset Information

CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts.

Publications

CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts.

Similar Datasets

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