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Background <p>Glioblastoma, the most common and aggressive primary brain malignancy, remains a lethal disease with limited therapeutic progress despite multimodal treatment. Although chimeric antigen receptor (CAR) T-cell therapy has shown promise in several solid tumors, its broader application in glioblastoma is limited by manufacturing hurdles of autologous T cells and the lack of validated tumor-specific antigens. As an alternative, gamma-delta (γδ) T cells have emerged as an attractive cellular platform, offering MHC-independent tumor recognition, robust ex vivo expansion, and suitability for allogeneic use. However, studies applying CAR engineering to γδ T cells in glioblastoma are extremely limited, and an optimal target antigen has not been clearly defined. In this context, our study identified B7-H3 as a clinically relevant target and demonstrated that B7-H3 CAR γδ T cells exhibited superior antitumor efficacy compared to unmodified γδ T cells across patient-derived and orthotopic glioblastoma models.</p> Methods <p>To identify an optimal antigen for γδ CAR-T therapy in glioblastoma, we compared the expression and clinical relevance of HER2, GD2, and B7-H3 through analyses of transcriptomic datasets and patient tumor samples. Based on this, human γδ T cells from healthy donors were expanded ex vivo, engineered with a B7-H3–specific CAR, and evaluated for antitumor activity across patient-derived glioblastoma cell lines, organoids, and orthotopic xenograft models.</p> Results <p>B7-H3 was identified as the most clinically relevant antigen, showing high expression in glioblastoma and correlated with poor prognosis and immunosuppressive gene signatures. B7-H3 CAR γδ T cells demonstrated potent cytotoxicity and enhanced cytokine production in B7-H3–high patient-derived glioblastoma models. In patient-derived organoids, CAR γδ T cells significantly reduced tumor viability and invasion. In orthotopic xenografts, a single intracranial administration induced tumor control and prolonged survival, with long-term survivors observed only in the CAR γδ T cell treated group. Across all preclinical models, B7-H3 CAR γδ T cells exerted superior antitumor efficacy compared with parental γδ T cells.</p> Conclusions <p>These findings suggest B7-H3 as a clinically meaningful and therapeutically targetable antigen in glioblastoma and demonstrate the potent preclinical efficacy of allogeneic B7-H3 CAR γδ T cells, supporting their development as a novel immunotherapeutic strategy for glioblastoma.</p>

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Efficacy of allogeneic B7-H3 CAR γδ T cells with comparative target assessment across preclinical models in glioblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Soohyeon Lee,
  • Soon-A Park,
  • Hantae Jo,
  • Dokyeong Kim,
  • Junseong Park,
  • Yeun-Jun Chung,
  • Sangmoo Jeong,
  • Yeong Hui Cho,
  • Heung Kyu Lee,
  • Stephen Ahn,
  • Haeyoun Choi

摘要

Background

Glioblastoma, the most common and aggressive primary brain malignancy, remains a lethal disease with limited therapeutic progress despite multimodal treatment. Although chimeric antigen receptor (CAR) T-cell therapy has shown promise in several solid tumors, its broader application in glioblastoma is limited by manufacturing hurdles of autologous T cells and the lack of validated tumor-specific antigens. As an alternative, gamma-delta (γδ) T cells have emerged as an attractive cellular platform, offering MHC-independent tumor recognition, robust ex vivo expansion, and suitability for allogeneic use. However, studies applying CAR engineering to γδ T cells in glioblastoma are extremely limited, and an optimal target antigen has not been clearly defined. In this context, our study identified B7-H3 as a clinically relevant target and demonstrated that B7-H3 CAR γδ T cells exhibited superior antitumor efficacy compared to unmodified γδ T cells across patient-derived and orthotopic glioblastoma models.

Methods

To identify an optimal antigen for γδ CAR-T therapy in glioblastoma, we compared the expression and clinical relevance of HER2, GD2, and B7-H3 through analyses of transcriptomic datasets and patient tumor samples. Based on this, human γδ T cells from healthy donors were expanded ex vivo, engineered with a B7-H3–specific CAR, and evaluated for antitumor activity across patient-derived glioblastoma cell lines, organoids, and orthotopic xenograft models.

Results

B7-H3 was identified as the most clinically relevant antigen, showing high expression in glioblastoma and correlated with poor prognosis and immunosuppressive gene signatures. B7-H3 CAR γδ T cells demonstrated potent cytotoxicity and enhanced cytokine production in B7-H3–high patient-derived glioblastoma models. In patient-derived organoids, CAR γδ T cells significantly reduced tumor viability and invasion. In orthotopic xenografts, a single intracranial administration induced tumor control and prolonged survival, with long-term survivors observed only in the CAR γδ T cell treated group. Across all preclinical models, B7-H3 CAR γδ T cells exerted superior antitumor efficacy compared with parental γδ T cells.

Conclusions

These findings suggest B7-H3 as a clinically meaningful and therapeutically targetable antigen in glioblastoma and demonstrate the potent preclinical efficacy of allogeneic B7-H3 CAR γδ T cells, supporting their development as a novel immunotherapeutic strategy for glioblastoma.