Novel B7-H3 CAR T cells show potent antitumor effects in glioblastoma: a preclinical study.

BACKGROUND

B7 homolog 3 (B7-H3), an overexpressed antigen across multiple solid cancers, represents a promising target for CAR T cell therapy. This study investigated the expression of B7-H3 across various solid tumors and developed novel monoclonal antibodies (mAbs) targeting B7-H3 for CAR T cell therapy.

METHODS

Expression of B7-H3 across various solid tumors was evaluated using RNA-seq data from TCGA, TARGET, and GTEx datasets and by flow cytometry staining. B7-H3-specific mAbs were developed by immunizing mice with human B7-H3, screening with ELISA, and analyzing kinetics with surface plasmon resonance. These mAbs were used to create second-generation CAR constructs, which were evaluated in vitro and in vivo for their antitumor function.

RESULTS

We identified four mAb clones from immunized mice, with three demonstrating high specificity and affinity. The second-generation B7-H3 CAR T cells derived from these mAbs exhibited robust cytotoxicity against B7-H3-positive targets and successfully infiltrated and eliminated tumor spheroids in vitro. In a xenograft mouse model of glioblastoma, these CAR T cells, particularly those derived from clone A2H4, eradicated the primary tumor, and effectively controlled rechallenge tumor, resulting in prolonged survival of the xenograft mice. In vivo T cell trafficking revealed high accumulation and persistence of A2H4-derived CAR T cells at the tumor site.

CONCLUSIONS

Our results provide novel B7-H3-targeted CAR T cells with high efficacy, paving the way for clinical translation of solid tumor treatment.