Efficacy of allogeneic B7-H3 CAR γδ T cells with comparative target assessment across preclinical models in glioblastoma
10 affiliations
- 1Department of Medical Sciences, Graduate School of The Catholic, University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591 Republic of Korea
- 2Department of Microbiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591 Republic of Korea
- 3Department of Neurosurgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591 Republic of Korea
- 4Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591 Republic of Korea
- 5Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591 Republic of Korea
- 6Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218 USA
- 7Institute for NanoBioTechnology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218 USA
- 8Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, MD 21205 Baltimore, United States of America
- 9Laboratory of Host Defenses, Department of Biological Sciences, Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Republic of Korea
- 10Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu Seoul, 06591, Republic of Korea
Abstract
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05121-2.
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BibTeX
@article{lee2026efficacy,
title = {{Efficacy of allogeneic B7-H3 CAR γδ T cells with comparative target assessment across preclinical models in glioblastoma}},
author = {Soohyeon Lee and Soon-A Park and Hantae Jo and Dokyeong Kim and Junseong Park and Yeun-Jun Chung and Sangmoo Jeong and Yeong Hui Cho and Heung Kyu Lee and Stephen Ahn and Haeyoun Choi},
journal = {BMC Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12916-026-05121-2},
url = {https://doi.org/10.1186/s12916-026-05121-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Efficacy of allogeneic B7-H3 CAR γδ T cells with comparative target assessment across preclinical models in glioblastoma
AU - Soohyeon Lee
AU - Soon-A Park
AU - Hantae Jo
AU - Dokyeong Kim
AU - Junseong Park
AU - Yeun-Jun Chung
AU - Sangmoo Jeong
AU - Yeong Hui Cho
AU - Heung Kyu Lee
AU - Stephen Ahn
AU - Haeyoun Choi
PY - 2026
DA - 2026/08/03
JO - BMC Medicine
DO - 10.1186/s12916-026-05121-2
UR - https://doi.org/10.1186/s12916-026-05121-2
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05121-2.
SN - 1741-7015
ER -