Mesothelin‑targeted second generation CAR‑T cells inhibit growth of mesothelin‑expressing tumors in vivo

Ye,Lin; Lou,Yuqing; Lu,Liming; Fan,Xiaohong

doi:10.3892/etm.2018.7015

January-2019 Volume 17 Issue 1

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January-2019 Volume 17 Issue 1

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Article Open Access

Mesothelin‑targeted second generation CAR‑T cells inhibit growth of mesothelin‑expressing tumors in vivo

Authors:
- Lin Ye
- Yuqing Lou
- Liming Lu
- Xiaohong Fan
View Affiliations / Copyright

Affiliations: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China

Copyright: © Ye et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 739-747
|
Published online on: November 27, 2018

https://doi.org/10.3892/etm.2018.7015
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Abstract

Non‑small cell lung cancer (NSCLC) and mesothelioma are renowned for being diagnosed at a late stage and poor prognosis. Although surgery, chemotherapy, and radiotherapy have yielded successful outcomes, the improvement on the survival rate of NSCLC and mesothelioma have been less marked. Recently, adoptive immunotherapy, particularly chimeric antigen receptor T (CAR‑T) cell therapy demonstrated promise for improving the survival of acute lymphoblastic leukemia with minimum toxicity. However, its application in solid tumors still warrants in‑depth investigations and multiple consistent trial results, particularly in eliminating ‘off‑tumor’ toxicity. To explore CAR‑T therapy in NSCLC and mesothelioma, second‑generation CAR‑T cells were constructed targeting mesothelin (MSLN), which is abundant in NSCLC and mesothelioma but is under expressed in normal tissues. The second‑generation design incorporated co‑stimulatory CD28 and 4‑1BB signaling domains to enhance the proliferation. Following the successful analysis of CAR‑T cells by flow cytometry, cytotoxicity experiments were performed using the LDH kit to verify the killing effect of CAR‑T cells on target cells. Otherwise, the in vivo killing tumor activity of MSLN CAR‑T cells was verified by constructing a mouse model using tumor‑derived cells from patients to inoculate the mice. When the effector‑to‑target ratio is >0.5:1, CAR‑T MSLN cells exhibited significantly higher ability to kill tumor cells than T cells. In in vivo experiments, mice whose tail vein was injected with CAR‑T MSLN cells demonstrated significantly slower tumor growth. Without continuous administration, both groups became gradually synchronized in growth of tumor size, which suggests that the persistence of CAR‑T cells is an important issue in preclinical studies.

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