c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells <i>in vitro</i> and <i>in vivo</i>

Xiaochen Huang; Jiaojiao Guo; Tao Li; Lizhou Jia; Xiaojun Tang; Jin Zhu; Qi Tang; Zhenqing Feng

doi:10.7555/JBR.35.20200207

Volume 36 Issue 1

Jan. 2022

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The Journal of Biomedical Research > 2022 > 36(1): 10-21. > DOI: 10.7555/JBR.35.20200207

Xiaochen Huang, Jiaojiao Guo, Tao Li, Lizhou Jia, Xiaojun Tang, Jin Zhu, Qi Tang, Zhenqing Feng. c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo[J]. The Journal of Biomedical Research, 2022, 36(1): 10-21. DOI: 10.7555/JBR.35.20200207

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c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo

Xiaochen Huang^{1, 2, 3},
Jiaojiao Guo^{1, 2},
Tao Li¹,
Lizhou Jia^{1, 2},
Xiaojun Tang¹,
Jin Zhu⁴,
Qi Tang^{1, 2, ,},
Zhenqing Feng^{1, 2, 5, ,}

1.
National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, Jiangsu 211166, China
2.
Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
3.
Departments of Pathology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Jiangsu Province Institute of Cancer, Nanjing, Jiangsu 210009, China
4.
Huadong Medical Institute of Biotechniques, Nanjing, Jiangsu 210002, China
5.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China

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Corresponding author:
Qi Tang, National Health Commission Key Laboratory of Antibody Techniques, Department of Pathology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869340, E-mail: qitang@njmu.edu.cn

Zhenqing Feng, National Health Commission Key Laboratory of Antibody Techniques, Department of Pathology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869340, E-mail: fengzhenqing@njmu.edu.cn
Received Date: December 07, 2020
Revised Date: September 02, 2021
Accepted Date: September 05, 2021
Available Online: December 15, 2021

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Abstract

Abstract

c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma (HCC). Therefore, c-Met may serve as a promising target for HCC immunotherapy. Modifying T cells to express c-Met-specific chimeric antigen receptor (CAR) is an attractive strategy in treating c-Met-positive HCC. This study aimed to systematically evaluate the inhibitory effects of 2^nd- and 3^rd-generation c-Met CAR-T cells on hepatocellular carcinoma (HCC) cells. Here, 2^nd- and 3^rd-generation c-Met CARs containing an anti-c-Met single-chain variable fragment (scFv) as well as the CD28 signaling domain and CD3ζ (c-Met-28-3ζ), the CD137 signaling domain and CD3ζ (c-Met-137-3ζ), or the CD28 and CD137 signaling domains and CD3ζ (c-Met-28-137-3ζ) were constructed, and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo. All c-Met CARs were stably expressed on T cell membrane, and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro. c-Met-28-137-3ζ CAR-T cells secreted more interferon-gamma (IFN-γ) and interleukin 2 (IL-2) than c-Met-28-3ζ CAR-T cells and c-Met-137-3ζ CAR-T cells. Compared with c-Met low-expressed cells, c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells. Moreover, c-Met-28-137-3ζ CAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups. This study suggests that 3^rd-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2^nd-generation c-Met CAR-T cells, thereby providing a promising therapeutic intervention for c-Met-positive HCC.
- chimeric antigen receptor,
- c-Met,
- hepatocellular carcinoma,
- immunotherapy

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References (31)

References

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c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo