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Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Recepto...

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Autores principales: Castelletti, Laura, Yeo, Dannel, van Zandwijk, Nico, Rasko, John E. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885509/
https://www.ncbi.nlm.nih.gov/pubmed/33588928
http://dx.doi.org/10.1186/s40364-021-00264-1
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author Castelletti, Laura
Yeo, Dannel
van Zandwijk, Nico
Rasko, John E. J.
author_facet Castelletti, Laura
Yeo, Dannel
van Zandwijk, Nico
Rasko, John E. J.
author_sort Castelletti, Laura
collection PubMed
description Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.
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spelling pubmed-78855092021-02-17 Anti-Mesothelin CAR T cell therapy for malignant mesothelioma Castelletti, Laura Yeo, Dannel van Zandwijk, Nico Rasko, John E. J. Biomark Res Review Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients. BioMed Central 2021-02-15 /pmc/articles/PMC7885509/ /pubmed/33588928 http://dx.doi.org/10.1186/s40364-021-00264-1 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Review
Castelletti, Laura
Yeo, Dannel
van Zandwijk, Nico
Rasko, John E. J.
Anti-Mesothelin CAR T cell therapy for malignant mesothelioma
title Anti-Mesothelin CAR T cell therapy for malignant mesothelioma
title_full Anti-Mesothelin CAR T cell therapy for malignant mesothelioma
title_fullStr Anti-Mesothelin CAR T cell therapy for malignant mesothelioma
title_full_unstemmed Anti-Mesothelin CAR T cell therapy for malignant mesothelioma
title_short Anti-Mesothelin CAR T cell therapy for malignant mesothelioma
title_sort anti-mesothelin car t cell therapy for malignant mesothelioma
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885509/
https://www.ncbi.nlm.nih.gov/pubmed/33588928
http://dx.doi.org/10.1186/s40364-021-00264-1
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