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A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Cell surface GRP78-directed CAR-T cells are effective at treating human pancreatic cancer in preclinical models
Yuncang Yuan1, Jiawei Fan1, Dandan Liang1
1Laboratory 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.
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.
Insights
Chimeric antigen receptor T (CAR-T) cell therapy targeting cell surface GRP78 (csGRP78) shows promise for pancreatic cancer. GRP78-CAR-T cells effectively suppressed tumor growth in vitro and in vivo, alone or with chemotherapy.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Pancreatic cancer is a lethal malignancy with limited therapeutic options.
- Chimeric antigen receptor T (CAR-T) cell therapy is effective in hematological cancers but faces challenges in solid tumors, including target scarcity.
- Cell surface GRP78 (csGRP78) is a promising tumor-selective target, highly expressed on pancreatic cancer cells but not normal cells.
Purpose of the Study:
- To evaluate the efficacy of csGRP78-directed CAR-T (GRP78-CAR-T) cells for pancreatic cancer treatment.
- To investigate the potential of GRP78-CAR-T cells as a monotherapy or in combination with chemotherapy.
Main Methods:
- In vitro cytotoxicity assays using luciferase-labeled pancreatic cancer cell lines and stem-like cells.
- In vivo mouse xenograft models to assess tumor homing, infiltration, and growth inhibition.
- Evaluation of combination therapy with gemcitabine and GRP78-CAR-T cells, including assessment of csGRP78 expression in resistant cells.
Main Results:
- GRP78-CAR-T cells demonstrated potent killing of pancreatic cancer cell lines and stem-like cells in vitro.
- GRP78-CAR-T cells effectively homed to pancreatic tumors and significantly inhibited tumor growth in vivo.
- Combination therapy with gemcitabine enhanced the cytotoxic effect on gemcitabine-resistant cells by increasing csGRP78 expression.
Conclusions:
- csGRP78 is a viable target for CAR-T cell therapy in pancreatic cancer.
- GRP78-CAR-T cells exhibit selective and efficient targeting of pancreatic tumors.
- Combining GRP78-CAR-T cells with chemotherapy offers a promising strategy to overcome treatment resistance and suppress pancreatic tumor growth.
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