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Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [RNA-Seq]

ABSTRACT: CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

ORGANISM(S): Mus musculus

PROVIDER: GSE158110 | GEO | 2020/09/18

REPOSITORIES: GEO

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Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [scRNA-Seq]

Project description:CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

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Mus musculus

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| PRJNA1130697 | ENA

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