Mesothelin-based CAR-T cells exhibit potent antitumor activity against ovarian cancer

Jing Guo; Xiaozhu Zeng; Yongjie Zhu; Dong Yang; Xudong Zhao

doi:10.1186/s12967-024-05174-y

Journal of Translational Medicine (Apr 2024)

Mesothelin-based CAR-T cells exhibit potent antitumor activity against ovarian cancer

Jing Guo,
Xiaozhu Zeng,
Yongjie Zhu,
Dong Yang,
Xudong Zhao

Affiliations

Jing Guo: Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University
Xiaozhu Zeng: Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University
Yongjie Zhu: Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University
Dong Yang: Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University
Xudong Zhao: Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University

DOI: https://doi.org/10.1186/s12967-024-05174-y
Journal volume & issue: Vol. 22, no. 1
pp. 1 – 15

Abstract

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Abstract Background Ovarian cancer (OC) is characterized by its rapid growth and spread which, accompanied by a low 5-year survival rate, necessitates the development of improved treatments. In ovarian cancer, the selective overexpression of Mucin-16 (MUC16, CA125) in tumor cells highlights its potential as a promising target for developing anti-tumor therapies. However, the potential effectiveness of CAR-T cell therapy that targets MUC16 in ovarian cancer cells is unknown. Methods The expression of MUC16 in viable OC cells was detected using immunofluorescence and flow cytometry techniques. A MSLN-CAR construct, comprising the MUC16-binding polypeptide region of mesothelin (MSLN), a CD8 hinge spacer and transmembrane domain, 4-1BB, and CD3ζ endo-domains; was synthesized and introduced into T cells using lentiviral particles. The cytotoxicity of the resultant CAR-T cells was evaluated in vitro using luciferase assays. Cytokine release by CAR-T cells was measured using enzyme-linked immunosorbent assays. The anti-tumor efficacy of the CAR-T cells was subsequently assessed in mice through both systemic and local administration protocols. Results MSLN-CAR T cells exhibited potent cytotoxicity towards OVCAR3 cells and their stem-like cells that express high levels of MUC16. Also, MSLN-CAR T cells were inefficient at killing SKOV3 cells that express low levels of MUC16, but were potently cytotoxic to such cells overexpressing MUC16. Moreover, MSLN-CAR T cells delivered via tail vein or peritoneal injection could shrink OVCAR3 xenograft tumors in vivo, with sustained remission observed following peritoneal delivery of MSLN-CAR T cells. Conclusions Collectively, these results suggested that MSLN-CAR T cells could potently eliminate MUC16- positive ovarian cancer tumor cells both in vitro and in vivo, thereby providing a promising therapeutic intervention for MUC16-positive patients.

Published in Journal of Translational Medicine

ISSN: 1479-5876 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine
Website: https://translational-medicine.biomedcentral.com/

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