Preconditioning of radiotherapy enhances efficacy of B7-H3-CAR-T in treating solid tumor models

Abstract

AimsLimited efficacy of chimeric antigen receptor T (CAR-T) cells in treating solid tumors is largely due to the antigen heterogeneity and immunosuppressive tumor microenvironment (TME). B7-H3 is over-expressed in most kind of solid tumors, making it a promising target for cancer treatment. This study aims to explore the effect of B7-H3-CAR-T therapy combined with radiotherapy in treating solid tumor models. MethodsIrradiated tumor cell lines were prepared and tested. A humanized B7-H3-CAR-T was constructed, and it was evaluated that B7-H3-CAR-T cytotoxicity against solid tumor models with preconditioning of radiotherapy in vitro and vivo. ResultsIrradiation was found to increase expression level of B7-H3 in pancreatic cancer (PANC-1), colorectal cancer (HCT-15, SW620), acute myelocytic leukemia (AML-5), epidermoid carcinoma (KB) and glioma (U87-MG) human cell lines significantly. 6Gy irradiation was also found to up-regulate tumor-infiltration molecule like intracellular adhesion molecule-1 ICAM-1 or FAS in HCT-15 cells, supporting a possible synergistic enhancement effect of radiotherapy. In vitro and in vivo experiments demonstrated that irradiation indeed significantly enhanced the ability of B7-H3-CAR-T to infiltrate and kill tumors. Interestingly in dual-tumor mouse model study, not only tumor cells on irradiation side were eradicated completely, irradiation also enhanced CAR-T tumor-killing ability on non-irradiated side, confirming the abscopal effect of irradiation existed with CAR-T therapy. ConclusionsOur results suggest that B7-H3-CAR-T therapy combined with radiotherapy may be a promising modality in treating solid tumors.