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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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