Hyper-migratory CAR T cells alleviate ovarian cancer metastatic burden and improve prognosis.

Cellular immunotherapy has shown remarkable efficacy in hematological malignancies but remains limited by infiltration issues in solid tumors, leading to poor treatment efficacy. We have recently shown that mesothelin-targeting CAR T cells co-transduced with cytokine-binding synthetic velocity receptors (VRs, referred to as CAR TV cells) demonstrate increased motility, improved infiltration in solid primary tumors, and lead to a better anti-tumor effect compared to CAR T cells that do not express VRs. However, it is metastasis that causes the vast majority of cancer related deaths and is difficult to target clinically, indicating an urgent unmet need. We show that these CAR T cells engineered to be hyper-migratory using VRs are highly effective against liver metastasis of ovarian cancer along different stages of the metastatic cascade. Mesothelin-targeting CAR TV cells expressing synthetic or native receptors responsive to the cytokine Interleukin-5 improved the survival of mice bearing an extremely high or 'terminal' level of metastatic burden compared to CAR T cells that did not express VRs. Against newly established metastatic lesions and lesions undergoing metastatic outgrowth, CAR TV cells showed a robust anti-cancer effect resulting in an improved prognosis compared to control CAR T cells. Histopathological assessments showed a substantial reduction of metastasis number and lesion size with CAR TV treatment, concomitant with increased immune cell infiltration in the metastatic regions. Our work demonstrates the efficacy of high-motility CAR T cells in a metastatic setting and extends their scope to the treatment of metastasis of solid tumors.