CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a highly aggressive and fatal pediatric brain tumor, with a median survival of only 18 months and no effective targeted therapies. While CAR T cell therapy has shown success in B-cell leukemia and promise in other pediatric CNS tumors, it has not yet been evaluated explicitly in preclinical or clinical models of DHG. B7-H3 (CD276), a tumor-associated antigen overexpressed in pediatric brain tumors, represents a promising target for immunotherapeutic intervention in DHG. Here, we present the first preclinical evaluation of B7-H3-directed CAR T cell therapy in DHG. METHODS: We evaluated B7-H3 expression in specimens from DHG patients and patient-derived cell lines. Two B7-H3-targeted CAR constructs were generated and evaluated for antigen-specific activation, cytokine production, exhaustion, and cytotoxicity in vitro. Therapeutic efficacy was assessed in multiple orthotopic DHG xenograft models, followed by multiplex immunofluorescence and serum cytokine profiling. RESULTS: B7-H3 was highly expressed in DHG tumors and cell lines, but at minimal levels in normal brain tissue. B7-H3 CAR T cells demonstrated potent, antigen-specific cytotoxicity against DHG cells, with negligible activity against B7-H3-knockout DHG cells. In vivo, the intratumoral administration of B7-H3 CAR T cells led to significant tumor regression and a substantial extension of survival in three DHG mouse models, with durable tumor eradication. CONCLUSION: This study provides preclinical evidence supporting B7-H3 CAR T cell therapy as a highly effective immunotherapeutic strategy for DHG. Our findings support B7-H3 as a compelling immunotherapeutic target for DHG, laying the groundwork for clinical translation. Diffuse hemispheric glioma (DHG) is an aggressive childhood brain tumor with limited treatment options and poor survival. In this study, we explored an immunotherapy approach using engineered immune cells, called CAR T cells, that specifically target a protein, B7-H3, found on tumor cells. We found that B7-H3 is highly present in DHG tumors but not in normal brain tissue. In brain tumor animal models, these CAR T cells effectively killed tumor cells, shrank tumors, and significantly extended survival. These findings offer promising evidence for a potential treatment option and support moving this approach toward clinical trials for children with DHG.