Utilizing a surgical resection model for evaluating mRNA-based multi-antigen targeting CAR-T cell therapy against solid tumors

Abstract Chimeric antigen receptor (CAR)-T cell therapies have demonstrated considerable remissions against hematological malignancies but only transient remission against glioblastoma. CAR-T cell engineering relies on viral transduction or nonviral delivery such as mRNA incorporation. However, current in vivo models are inadequate for mRNA-based CAR-T cell evaluation due to short-term CAR expression. Here, we investigated multi-antigen targeting mRNA-based CAR-T cells locally injected in a xenograft mouse model after surgical resection of primary tumor. NSG mice, subcutaneously inoculated with glioma cells, were divided into groups receiving either mock T or CAR-T cells. A resection cutoff of minimal residual disease was used to subdivide mice based on resection intensity (desired or undesired). Anti-tumor cytotoxicity was both resection- and dose-dependent. Notably, >75% of mice undergoing undesired resection succumbed 49 days post-resection. However, CAR-T cell treated mice undergoing desired resection demonstrated complete or partial remissions along with significantly higher survival rates. Treatment of resection models with multivariant mRNA-based CAR-T cells demonstrates the translational utility of nonviral CAR-T cell approaches, building on previous reports targeting multiple antigens to offset solid tumor evasion. To sum up, our xenograft resection/CAR-T cell model is better tailored for evaluation of mRNA-based CAR-T cell therapies against solid tumors than existing models.