The antitumor capacity of mesothelin-CAR-T cells in targeting solid tumors in mice

• Main Authors: Qian Zhang, Guoping Liu, Jibin Liu, Mu Yang, Juan Fu, Guodi Liu, Dehua Li, Zhangjie Gu, Linsong Zhang, Yingjiao Pan, Xingbing Cui, Lu Wang, Lixin Zhang, Xiaoli Tian
• Format: Article
• Language: English
• Published: Elsevier 2021-03-01
• Series: Molecular Therapy: Oncolytics
• Subjects: ▪▪▪
• Online Access: http://www.sciencedirect.com/science/article/pii/S2372770521000310

Since the approval of chimeric antigen receptor (CAR) T cell therapy targeting CD19 by the FDA, CAR-T cell therapy has received increasing attention as a new method for targeting tumors. Although CAR-T cell therapy has a good effect against hematological malignancies, it has been less effective against solid tumors. In the present study, we selected mesothelin (MSLN/MESO) as a target for CAR-T cells because it is highly expressed by solid tumors but only expressed at low levels by normal tissues. We engineered a third generation MSLN-CAR comprising a single-chain variable fragment (scFv) targeting MSLN (MSLN-scFv), a CD8 transmembrane domain, the costimulatory domains from CD28 and 4-1BB, and the activating domain CD3ζ. In vitro, MSLN-CAR-T cells killed various solid tumor cell lines, demonstrating that it could specifically kill MSLN-positive cells and release cytokines. In vivo, we investigated the effects of MSLN-CAR-T cell therapy against ovarian, breast, and colorectal cancer cell-line-derived xenografts (CDX) and MSLN-positive colorectal and gastric cancer patient-derived xenografts (PDX). MSLN-CAR decreased the growth of MSLN-positive tumors concomitant with significantly increased T cells and cytokine levels compared to the control group. These results indicated that modified MSLN-CAR-T cells could be a promising therapeutic approach for solid tumors.