Title: | Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
Authors: | Sato, Osamu Browse this author |
Tsuchikawa, Takahiro Browse this author →KAKEN DB |
Kato, Takuma Browse this author |
Amaishi, Yasunori Browse this author |
Okamoto, Sachiko Browse this author |
Mineno, Junichi Browse this author |
Takeuchi, Yuta Browse this author |
Sasaki, Katsunori Browse this author |
Nakamura, Toru Browse this author |
Umemoto, Kazufumi Browse this author |
Suzuki, Tomohiro Browse this author |
Wang, Linan Browse this author |
Wang, Yizheng Browse this author |
Hatanaka, Kanako C. Browse this author |
Mitsuhashi, Tomoko Browse this author |
Hatanaka, Yutaka Browse this author |
Shiku, Hiroshi Browse this author |
Hirano, Satoshi Browse this author →KAKEN DB |
Keywords: | chimeric antigen receptor engineered T cell |
carcinoembryonic antigen |
pancreatic ductal carcinoma |
adoptive cell therapy |
orthotopic xenograft mouse model |
Issue Date: | Feb-2023 |
Publisher: | MDPI |
Journal Title: | Cancers |
Volume: | 15 |
Issue: | 3 |
Start Page: | 601 |
Publisher DOI: | 10.3390/cancers15030601 |
Abstract: | Simple Summary Pancreatic ductal adenocarcinoma is one of the most lethal malignancies, and there are vast unmet medical needs. In this study, we hypothesized that chimeric antigen receptor engineered T cell (CAR-T) targeting carcinoembryonic antigen (CEA) would be effective in the treatment of pancreatic ductal adenocarcinoma. In vivo experiments in a more clinically similar environment were considered necessary; we examined the antitumor effects of adoptive anti-CEA-CAR-T, using orthotopic xenograft mouse models of pancreatic ductal adenocarcinoma. As result, the therapeutic effect of anti-CEA-CAR-T therapy was related to the CEA expression level. Furthermore, the retrospective analysis of pathological findings from pancreatic ductal adenocarcinoma patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. These findings show that anti-CEA-CAR-T therapy can be useful for pancreatic ductal adenocarcinoma; furthermore, the pathological findings of CEA can be clinically used as biomarkers to select cases for anti-CEA-CAR-T therapy. Chimeric antigen receptor engineered T cell (CAR-T) therapy has high therapeutic efficacy against blood cancers, but it has not shown satisfactory results in solid tumors. Therefore, we examined the therapeutic effect of CAR-T therapy targeting carcinoembryonic antigen (CEA) in pancreatic adenocarcinoma (PDAC). CEA expression levels on the cell membranes of various PDAC cell lines were evaluated using flow cytometry and the cells were divided into high, medium, and low expression groups. The relationship between CEA expression level and the antitumor effect of anti-CEA-CAR-T was evaluated using a functional assay for various PDAC cell lines; a significant correlation was observed between CEA expression level and the antitumor effect. We created orthotopic PDAC xenograft mouse models and injected with anti-CEA-CAR-T; only the cell line with high CEA expression exhibited a significant therapeutic effect. Thus, the therapeutic effect of CAR-T therapy was related to the target antigen expression level, and the further retrospective analysis of pathological findings from PDAC patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. Therefore, CEA expression levels in biopsies or surgical specimens can be clinically used as biomarkers to select PDAC patients for anti-CAR-T therapy. |
Type: | article |
URI: | http://hdl.handle.net/2115/88802 |
Appears in Collections: | 北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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