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

Highlights

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  GRP78-CAR-T cells killed human pancreatic cancer cell lines.

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  GRP78- CAR-t cells lysis human pancreatic cancer stem-like cells.

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  GRP78-CAR-T cells eradicate human pancreatic cancer in a mouse xenograft model.

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  GRP78-CAR-T cells overcomes gemcitabine resistance in pancreatic cancer.

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.