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Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma

T cells expressing chimeric antigen receptors, especially CD19 CAR-T cells have exhibited effective antitumor activities in B cell malignancies, but due to several factors such as antigen escape effects and tumor microenvironment, their curative potential in hepatocellular carcinoma has not been enc...

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Autores principales: Jiang, Wei, Li, Tao, Guo, Jiaojiao, Wang, Jingjing, Jia, Lizhou, shi, Xiao, Yang, Tingting, Jiao, Ruonan, Wei, Xin, Feng, Zhenqing, Tang, Qi, Ji, Guozhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987916/
https://www.ncbi.nlm.nih.gov/pubmed/33777728
http://dx.doi.org/10.3389/fonc.2021.546586
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author Jiang, Wei
Li, Tao
Guo, Jiaojiao
Wang, Jingjing
Jia, Lizhou
shi, Xiao
Yang, Tingting
Jiao, Ruonan
Wei, Xin
Feng, Zhenqing
Tang, Qi
Ji, Guozhong
author_facet Jiang, Wei
Li, Tao
Guo, Jiaojiao
Wang, Jingjing
Jia, Lizhou
shi, Xiao
Yang, Tingting
Jiao, Ruonan
Wei, Xin
Feng, Zhenqing
Tang, Qi
Ji, Guozhong
author_sort Jiang, Wei
collection PubMed
description T cells expressing chimeric antigen receptors, especially CD19 CAR-T cells have exhibited effective antitumor activities in B cell malignancies, but due to several factors such as antigen escape effects and tumor microenvironment, their curative potential in hepatocellular carcinoma has not been encouraging. To reduce the antigen escape risk of hepatocellular carcinoma, this study was to design and construct a bispecific CAR targeting c-Met and PD-L1. c-Met/PD-L1 CAR-T cells were obtained by lentiviral transfection, and the transfection efficiency was monitored by flow cytometry analysis. LDH release assays were used to elucidate the efficacy of c-Met/PD-L1 CAR-T cells on hepatocellular carcinoma cells. In addition, xenograft models bearing human hepatocellular carcinoma were constructed to detect the antitumor effect of c-Met/PD-L1 CAR-T cells in vivo. The results shown that this bispecific CAR was manufactured successfully, T cells modified with this bispecific CAR demonstrated improved antitumor activities against c-Met and PD-L1 positive hepatocellular carcinoma cells when compared with those of monovalent c-Met CAR-T cells or PD-L1 CAR-T cells but shown no distinct cytotoxicity on hepatocytes in vitro. In vivo experiments shown that c-Met/PD-L1 CAR-T cells significantly inhibited tumor growth and improve survival persistence compared with other groups. These results suggested that the design of single-chain, bi-specific c-Met/PD-L1 CAR-T is more effective than that of monovalent c-Met CAR-T for the treatment of hepatocellular carcinoma., and this bi-specific c-Met/PD-L1 CAR is rational and implementable with current T-cell engineering technology.
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spelling pubmed-79879162021-03-25 Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma Jiang, Wei Li, Tao Guo, Jiaojiao Wang, Jingjing Jia, Lizhou shi, Xiao Yang, Tingting Jiao, Ruonan Wei, Xin Feng, Zhenqing Tang, Qi Ji, Guozhong Front Oncol Oncology T cells expressing chimeric antigen receptors, especially CD19 CAR-T cells have exhibited effective antitumor activities in B cell malignancies, but due to several factors such as antigen escape effects and tumor microenvironment, their curative potential in hepatocellular carcinoma has not been encouraging. To reduce the antigen escape risk of hepatocellular carcinoma, this study was to design and construct a bispecific CAR targeting c-Met and PD-L1. c-Met/PD-L1 CAR-T cells were obtained by lentiviral transfection, and the transfection efficiency was monitored by flow cytometry analysis. LDH release assays were used to elucidate the efficacy of c-Met/PD-L1 CAR-T cells on hepatocellular carcinoma cells. In addition, xenograft models bearing human hepatocellular carcinoma were constructed to detect the antitumor effect of c-Met/PD-L1 CAR-T cells in vivo. The results shown that this bispecific CAR was manufactured successfully, T cells modified with this bispecific CAR demonstrated improved antitumor activities against c-Met and PD-L1 positive hepatocellular carcinoma cells when compared with those of monovalent c-Met CAR-T cells or PD-L1 CAR-T cells but shown no distinct cytotoxicity on hepatocytes in vitro. In vivo experiments shown that c-Met/PD-L1 CAR-T cells significantly inhibited tumor growth and improve survival persistence compared with other groups. These results suggested that the design of single-chain, bi-specific c-Met/PD-L1 CAR-T is more effective than that of monovalent c-Met CAR-T for the treatment of hepatocellular carcinoma., and this bi-specific c-Met/PD-L1 CAR is rational and implementable with current T-cell engineering technology. Frontiers Media S.A. 2021-03-10 /pmc/articles/PMC7987916/ /pubmed/33777728 http://dx.doi.org/10.3389/fonc.2021.546586 Text en Copyright © 2021 Jiang, Li, Guo, Wang, Jia, shi, Yang, Jiao, Wei, Feng, Tang and Ji http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Jiang, Wei
Li, Tao
Guo, Jiaojiao
Wang, Jingjing
Jia, Lizhou
shi, Xiao
Yang, Tingting
Jiao, Ruonan
Wei, Xin
Feng, Zhenqing
Tang, Qi
Ji, Guozhong
Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma
title Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma
title_full Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma
title_fullStr Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma
title_full_unstemmed Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma
title_short Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma
title_sort bispecific c-met/pd-l1 car-t cells have enhanced therapeutic effects on hepatocellular carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987916/
https://www.ncbi.nlm.nih.gov/pubmed/33777728
http://dx.doi.org/10.3389/fonc.2021.546586
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