Cell surface GRP78-directed CAR-T cells are effective at treating human pancreatic cancer in preclinical models

Yuncang Yuan; Jiawei Fan; Dandan Liang; Shijie Wang; Xu Luo; Yongjie Zhu; Nan Liu; Tingxiu Xiang; Xudong Zhao

doi:10.1016/j.tranon.2023.101803

Cell surface GRP78-directed CAR-T cells are effective at treating human pancreatic cancer in preclinical models

Transl Oncol. 2024 Jan:39:101803. doi: 10.1016/j.tranon.2023.101803. Epub 2023 Oct 26.

Authors

Yuncang Yuan¹, Jiawei Fan¹, Dandan Liang¹, Shijie Wang¹, Xu Luo², Yongjie Zhu¹, Nan Liu¹, Tingxiu Xiang³, Xudong Zhao⁴

Affiliations

¹ Laboratory of Animal Tumor Models, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
² Development and Application of Human Major Disease Monkey Model Key Laboratory of Sichuan Province, Sichuan Hengshu Bio-Technology Co., Ltd., Yibin 644600, China.
³ Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China. Electronic address: xiangtx@cqmu.edu.cn.
⁴ Laboratory of Animal Tumor Models, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: zhaoxudong@wchscu.cn.

Abstract

Pancreatic cancer is a highly lethal solid malignancy with limited treatment options. Chimeric antigen receptor T (CAR-T) cell therapy has been successfully applied to treat hematological malignancies, but faces many challenges in solid tumors. One major challenge is the shortage of tumor-selective targets. Cell surface GRP78 (csGRP78) is highly expressed on various solid cancer cells including pancreatic cancer, but not normal cells, providing a potential target for CAR-T cell therapy in pancreatic cancer. Here, we demonstrated that csGRP78-directed CAR-T (GRP78-CAR-T) cells effectively killed the human pancreatic cancer cell lines Bxpc-3-luc, Aspc-1-luc and MIA PaCa-2-luc, and pancreatic cancer stem-like cells derived from Aspc-1-luc cells and MIA PaCa-2-luc cells in vitro by a luciferase-based cytotoxicity assay. Importantly, we showed that GRP78-CAR-T cells efficiently homed to and infiltrated Aspc-1-luc cell-derived xenografts and significantly inhibited pancreatic tumor growth in vivo by performing mouse xenograft experiments. Interestingly, we found that gemcitabine treatment increased csGRP78 expression in gemcitabine-resistant MIA PaCa-2-luc cells, and the coapplication of gemcitabine with GRP78-CAR-T cells led to a robust cytotoxic effect on these cells in vitro. Taken together, our study demonstrates that csGRP78-directed CAR-T cells, alone or in combination with chemotherapy, selectively and efficiently target csGRP78-expressing pancreatic cancer cells to suppress pancreatic tumor growth.

Keywords: CAR-T; Gemcitabine; Pancreatic cancer; csGRP78.