Preclinical development of mesothelin-targeting CAR T cells for the treatment of cholangiocarcinoma
Issued Date
2026-02-01
Resource Type
eISSN
2471254X
Scopus ID
2-s2.0-105036204450
Pubmed ID
41543488
Journal Title
Hepatology Communications
Volume
10
Issue
2
Rights Holder(s)
SCOPUS
Bibliographic Citation
Hepatology Communications Vol.10 No.2 (2026)
Suggested Citation
Duangdara J., Lin S., Hong J., Li D., Suriyonplengsaeng C., Larbcharoensub N., Wongprasert K., Ho M. Preclinical development of mesothelin-targeting CAR T cells for the treatment of cholangiocarcinoma. Hepatology Communications Vol.10 No.2 (2026). doi:10.1097/HC9.0000000000000888 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/116435
Title
Preclinical development of mesothelin-targeting CAR T cells for the treatment of cholangiocarcinoma
Corresponding Author(s)
Other Contributor(s)
Abstract
Background: – Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematological malignancies. However, the complex tumor microenvironment of cholangiocarcinoma (CCA) poses significant challenges, particularly due to the lack of clinically validated targets and the presence of fibrosis, which hinders T cell infiltration into tumor sites. Mesothelin (MSLN) is highly expressed in CCA. In this study, we aimed to develop CAR T therapy based on a panel of humanized rabbit monoclonal antibodies targeting various epitopes of MSLN, ranging from the N- to the C-terminus, for CCA. Methods: – MSLN expression was assessed in CCA tissue samples obtained from Thai patients. CAR T cells were generated using various single-chain variable fragment (scFv) constructs, engineered in either VH-linker-VL or VL-linker-VH orientation, targeting non-overlapping epitopes of membrane-bound MSLN: hYP218 (proximal region), hYP223 and hYP3 (middle region), and hYP158 (distal region). The cytotoxicity of MSLN-specific CAR T cells was evaluated in 3 preclinical CCA mouse models: Mz-ChA-1, KMCH, and KMBC. Results: – MSLN was strongly expressed in 79% of the CCA specimens. Among the CAR constructs, hYP218-based CAR T cells—with the VL-linker-VH orientation and CD28-derived hinge and transmembrane domains (CD28HTM)—completely eradicated CCA tumors in all 3 CCA xenograft mouse models (Mz-ChA-1, KMCH, and KMBC). Furthermore, hYP218 VLVH CD28HTM CAR T cells showed strong persistence in mice, with low PD-1 expression (a marker of T cell exhaustion) and minimal adverse effects. Conclusions: – Our findings suggest that MSLN is a promising target for CAR T cell therapy in CCA. CAR T cells engineered with hYP218 VLVH CD28HTM, which targets the membrane-proximal epitope of MSLN, may represent a novel therapeutic strategy for the clinical treatment of CCA.