Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor
By Zhiwei Zhang, Duqing Jiang, Huan Yang, Zhou He, Xiangzhen Liu, W. Qin, Linfang Li, Chao Wang, Yang Li, He Li and 3 more. 2019
108 citations recorded by the source corpus.
Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known as a membrane-proximal region) using a modified piggyBac transposon system. We reported that, compared with meso1 CAR T cells, meso3 CAR T cells express higher levels of CD107α upon activation and produce increased levels of interleukin-2, TNF-α, and IFN-γ against multiple MSLN-expressing cancer cells in vitro. In a real-time cell analyzer system and a three-dimensional spheroid cancer cell model, we also demonstrated that meso3 CAR T cells display an enhanced killing effect compared with that of meso1 CAR T cells. More importantly, in a gastric cancer NSG mice model, meso3 CAR T cells mediated stronger antitumor responses than meso1 CAR T cells did. We further identified that meso3 CAR T cells can effectively inhibit the growth of large ovarian tumors in vivo. Collectively, our study provides evidences that meso3 CAR T-cell therapy performs as a better immunotherapy than meso1 CAR T-cell therapy in treating MSLN-positive solid tumors.
Subfields: Genetics, Molecular Biology, Oncology
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Citations in the corpus
- Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors (2020, background): “In addition, by comparing two types of CAR-T cells targeting either the region-I or the region-III ofMSLN, Qian and colleagues demonstrated recently that the membrane-proximal region of MSLN is a promising epitope to target for solid tumor using CAR T-cell therapy.(40) The precise conditions that de”
- Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma (2021, background): “An in vitro study showed that a MSLN-targeted therapy targeting region III had stronger activation and cytotoxicity compared to that targeting region I [92].”