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

• Published in: Translational oncology 2024-01, Vol.39, p.101803-101803, Article 101803
• Main Authors: Yuan, Yuncang, Fan, Jiawei, Liang, Dandan, Wang, Shijie, Luo, Xu, Zhu, Yongjie, Liu, Nan, Xiang, Tingxiu, Zhao, Xudong
• Format: Article
• Language: English
• Subjects: CAR-T; csGRP78; Gemcitabine; Pancreatic cancer
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2023.101803

•GRP78-CAR-T cells killed human pancreatic cancer cell lines•GRP78- CAR-T cells lysis human pancreatic cancer stem-like cells•GRP78-CAR-T cells eradicate human pancreatic cancer in a mouse xenograft model•GRP78-CAR-T cells overcomes gemcitabine resistance in pancreatic cancer 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.