Int J Biol Sci 2021; 17(14):3850-3861. doi:10.7150/ijbs.64630 This issue

Research Paper

Development of mesothelin-specific CAR NK-92 cells for the treatment of gastric cancer

Bihui Cao1✉#, Manting Liu1✉#, Jingjun Huang1#, Jingwen Zhou1#, Junping Li1#, Hui Lian1, Wensou Huang1, Yongjian Guo1, Shuo Yang4, Liteng Lin1, Mingyue Cai1, Cheng Zhi3, Jingqiang Wu1, Licong Liang1, Yuling Hu1, Hong Hu1, Jinping He1, Baoxia Liang1✉, Qi Zhao2✉, Kangshun Zhu1✉

1. Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China.
2. MoE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, 999078 China.
3. Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
4. Department of Pharmacy, Guangzhou Medical University, 511436, China.
#These authors contributed equally to this study.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Cao B, Liu M, Huang J, Zhou J, Li J, Lian H, Huang W, Guo Y, Yang S, Lin L, Cai M, Zhi C, Wu J, Liang L, Hu Y, Hu H, He J, Liang B, Zhao Q, Zhu K. Development of mesothelin-specific CAR NK-92 cells for the treatment of gastric cancer. Int J Biol Sci 2021; 17(14):3850-3861. doi:10.7150/ijbs.64630. Available from https://www.ijbs.com/v17p3850.htm

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Abstract

Graphic abstract

Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR NK cell efficacy. It has been reported that mesothelin (MSLN) may be an ideal immunotherapy target for gastric cancer. However, the feasibility of using anti-MSLN CAR NK cells to treat gastric cancer remains to be studied.

Methods: MSLN expression in primary human gastric cancer, normal tissues and cell lines were detected. MSLN and CD19 targeted CAR NK-92 (MSLN- and CD19-CAR NK) cells were constructed, purified and verified. N87, MKN-28, AGS and Huh-7 cells expressing the GFP and luciferase genes were transduced. Cell- and patient-derived xenograft (PDX) were established via NSG mice. The ability of MSLN-CAR NK cells to kill MSLN-positive gastric cancer cells were evaluated in vitro and in vivo.

Results: MSLN-CAR NK cells can specifically kill MSLN-positive gastric cancer cells (N87, MKN-28 and AGS), rather than MSLN negative cell (Huh-7), in vitro. Moreover, compared with parental NK-92 cells and CD19-CAR NK cells, stronger cytokine secretions were secreted in MSLN-CAR NK cells cocultured with N87, MKN-28 and AGS. Furthermore, MSLN-CAR NK cells can effectively eliminate gastric cancer cells in both subcutaneous and intraperitoneal tumor models. They could also significantly prolong the survival of intraperitoneally tumor-bearing mice. More importantly, the potent antitumor effect and considerable NK cell infiltration were observed in the patient-derived xenograft treated with MSLN-CAR NK cells, which further warranted the therapeutic effects of MSLN-CAR NK cells to treat gastric cancer.

Conclusion: These results demonstrate that MSLN-CAR NK cells possess strong antitumor activity and represent a promising therapeutic approach to gastric cancer.

Keywords: Gastric cancer, mesothelin, chimeric antigen receptor, NK-92, PDX