Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade

Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates 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 improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic. [Display omitted] •ROR1 CAR-T cells infiltrate breast and lung tumors poorly and became dysfunctional•Oxaliplatin (Ox) activates tumor macrophages to express chemokines recruiting CAR-T cells•CAR-T cells remodel the tumor microenvironment to amplify recruitment of T cells•Ox improves CAR-T cell infiltration, tumor response to anti-PD-L1, and survival Srivastava et al. demonstrate that adding oxaliplatin to the lymphodepletion regimen given before CAR-T cell infusion activates lung tumor macrophages to produce T-cell-recruiting chemokines. This results in improved CAR-T cell infiltration, tumor remodeling, and response to checkpoint blockade, providing a strategy to improve CAR-T cell efficacy in the clinic.