PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cells in lung cancer brain metastasis.

Abstract

Background Lung cancer brain metastasis have a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cells show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD1 antibodies on CAR T-cells in treating lung cancer brain metastasis. Methods We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy (TPLSM), enabling in vivo characterization of red fluorescent tumor cells and CAR T-cells at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (^EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cells were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control. Results Compared to controls receiving T-cells lacking a CAR, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect. Conclusion CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.