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Updated: Jul 22, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
GAS6-based CAR-T cells exhibit potent antitumor activity against pancreatic cancer
Jiawei Fan1, Ye Yu1, Lanzhen Yan1
1Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Background:
The receptor tyrosine kinases TAM family (TYRO3, AXL, and MERTK) are highly expressed in multiple forms of cancer cells and tumor-associated macrophages and promote the development of cancers including pancreatic tumor. Targeting TAM receptors could be a promising therapeutic option.
Methods:
We designed a novel CAR based on the extracellular domain of growth arrest-specific protein 6 (GAS6), a natural ligand for all TAM members. The ability of CAR-T to kill pancreatic cancer cells is tested in vitro and in vivo, and the safety is evaluated in mice and nonhuman primate.
Results:
GAS6-CAR-T cells efficiently kill TAM-positive pancreatic cancer cell lines, gemcitabine-resistant cancer cells, and cancer stem-like cells in vitro. GAS6-CAR-T cells also significantly suppressed the growth of PANC1 xenografts and patient-derived xenografts in mice. Furthermore, these CAR-T cells did not induce obvious side effects in nonhuman primate or mice although the CAR was demonstrated to recognize mouse TAM.
Conclusions:
Our findings indicate that GAS6-CAR-T-cell therapy may be effective for pancreatic cancers with low toxicity.
Insights
Novel GAS6-CAR-T-cell therapy shows promise for pancreatic cancer. This treatment effectively targets TAM-positive and resistant cancer cells with minimal toxicity in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- TAM receptor tyrosine kinases (TYRO3, AXL, MERTK) are upregulated in pancreatic cancer and associated macrophages.
- Targeting TAM receptors presents a potential therapeutic strategy for pancreatic cancer treatment.
Purpose of the Study:
- To develop and evaluate a novel Chimeric Antigen Receptor T-cell (CAR-T) therapy targeting TAM receptors.
- To assess the efficacy and safety of GAS6-CAR-T cells against pancreatic cancer.
Main Methods:
- Designed a CAR-T construct utilizing the GAS6 ligand, which binds to TAM receptors.
- Tested GAS6-CAR-T cell efficacy against pancreatic cancer cell lines in vitro and in vivo.
- Evaluated the safety profile of GAS6-CAR-T cells in mouse and nonhuman primate models.
Main Results:
- GAS6-CAR-T cells demonstrated potent killing of TAM-positive, gemcitabine-resistant, and cancer stem-like pancreatic cells in vitro.
- Significant suppression of pancreatic tumor growth (PANC1 and patient-derived xenografts) was observed in vivo.
- GAS6-CAR-T cells exhibited a favorable safety profile with no obvious adverse effects in preclinical models.
Conclusions:
- GAS6-CAR-T-cell therapy is a promising approach for treating pancreatic cancer.
- This therapy offers potential efficacy against various pancreatic cancer subtypes with low toxicity.
