Neuro-oncology · 2026
Potent anti-tumor preclinical efficacy of B7-H3 CAR-T cells in H3G34-mutant, Diffuse Hemispheric Glioma.
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Akhavan David, Yadav Monika, Subham Siddharth, Jeppson John, Tinoco Omar, Chin Scott, Santana-Magal Nadine, Babai Jacqueline, Szarejko John, Gibson Garrett, Sabitov Kirill, Zamler Daniel B, Myers G Doug, Fridley Brooke L, Bossmann Stefan H, Pyaram Kalyani, Yadav Viveka Nand
Аннотация
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.
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.