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Potent anti-tumor preclinical efficacy of B7-H3 CAR-T cells in H3G34-mutant, Diffuse Hemispheric Glioma
David Akhavan1, Monika Yadav2, Siddharth Subham1
1Department of Radiation Oncology, University of Kansas Cancer Center, Kansas City, KS, USA.
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.
Insights
CAR T cell therapy targeting B7-H3 shows promise for Diffuse Hemispheric Glioma (DHG). This preclinical study demonstrated significant tumor regression and extended survival in DHG models, supporting B7-H3 as a viable therapeutic target.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Neuro-oncology
Background:
- Diffuse Hemispheric Glioma (DHG) is an aggressive pediatric brain tumor with poor prognosis.
- Current treatments for DHG are limited, with a median survival of approximately 18 months.
- Chimeric Antigen Receptor (CAR) T cell therapy is a promising approach for various cancers and pediatric central nervous system tumors.
Purpose of the Study:
- To evaluate the potential of B7-H3-directed CAR T cell therapy in Diffuse Hemispheric Glioma (DHG).
- To assess B7-H3 expression in DHG tumors and its suitability as a therapeutic target.
- To determine the preclinical efficacy of B7-H3 CAR T cells in DHG models.
Main Methods:
- Assessed B7-H3 expression in DHG patient specimens and cell lines.
- Developed and tested two B7-H3-targeted CAR constructs for in vitro activity.
- Evaluated therapeutic efficacy in orthotopic DHG xenograft models, including tumor regression and survival analysis.
Main Results:
- B7-H3 was highly expressed in DHG tumors and cell lines, with minimal expression in normal brain tissue.
- B7-H3 CAR T cells exhibited potent, antigen-specific cytotoxicity against DHG cells in vitro.
- Intratumoral administration of B7-H3 CAR T cells resulted in significant tumor regression and durable tumor eradication in DHG mouse models.
Conclusions:
- B7-H3 CAR T cell therapy demonstrates significant preclinical efficacy against Diffuse Hemispheric Glioma (DHG).
- B7-H3 is a promising immunotherapeutic target for DHG, supporting further clinical investigation.
- These findings lay the foundation for the clinical translation of B7-H3 CAR T cell therapy for DHG patients.
