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Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells
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 pan...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913141/ https://www.ncbi.nlm.nih.gov/pubmed/36765558 http://dx.doi.org/10.3390/cancers15030601 |
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author | Sato, Osamu Tsuchikawa, Takahiro Kato, Takuma Amaishi, Yasunori Okamoto, Sachiko Mineno, Junichi Takeuchi, Yuta Sasaki, Katsunori Nakamura, Toru Umemoto, Kazufumi Suzuki, Tomohiro Wang, Linan Wang, Yizheng Hatanaka, Kanako C. Mitsuhashi, Tomoko Hatanaka, Yutaka Shiku, Hiroshi Hirano, Satoshi |
author_facet | Sato, Osamu Tsuchikawa, Takahiro Kato, Takuma Amaishi, Yasunori Okamoto, Sachiko Mineno, Junichi Takeuchi, Yuta Sasaki, Katsunori Nakamura, Toru Umemoto, Kazufumi Suzuki, Tomohiro Wang, Linan Wang, Yizheng Hatanaka, Kanako C. Mitsuhashi, Tomoko Hatanaka, Yutaka Shiku, Hiroshi Hirano, Satoshi |
author_sort | Sato, Osamu |
collection | PubMed |
description | 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. ABSTRACT: 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. |
format | Online Article Text |
id | pubmed-9913141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99131412023-02-11 Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells Sato, Osamu Tsuchikawa, Takahiro Kato, Takuma Amaishi, Yasunori Okamoto, Sachiko Mineno, Junichi Takeuchi, Yuta Sasaki, Katsunori Nakamura, Toru Umemoto, Kazufumi Suzuki, Tomohiro Wang, Linan Wang, Yizheng Hatanaka, Kanako C. Mitsuhashi, Tomoko Hatanaka, Yutaka Shiku, Hiroshi Hirano, Satoshi Cancers (Basel) Article 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. ABSTRACT: 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. MDPI 2023-01-18 /pmc/articles/PMC9913141/ /pubmed/36765558 http://dx.doi.org/10.3390/cancers15030601 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sato, Osamu Tsuchikawa, Takahiro Kato, Takuma Amaishi, Yasunori Okamoto, Sachiko Mineno, Junichi Takeuchi, Yuta Sasaki, Katsunori Nakamura, Toru Umemoto, Kazufumi Suzuki, Tomohiro Wang, Linan Wang, Yizheng Hatanaka, Kanako C. Mitsuhashi, Tomoko Hatanaka, Yutaka Shiku, Hiroshi Hirano, Satoshi Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
title | Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
title_full | Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
title_fullStr | Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
title_full_unstemmed | Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
title_short | Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells |
title_sort | tumor growth suppression of pancreatic cancer orthotopic xenograft model by cea-targeting car-t cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913141/ https://www.ncbi.nlm.nih.gov/pubmed/36765558 http://dx.doi.org/10.3390/cancers15030601 |
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