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Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide a...

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Autores principales: Sachdeva, Mohit, Busser, Brian W., Temburni, Sonal, Jahangiri, Billal, Gautron, Anne-Sophie, Maréchal, Alan, Juillerat, Alexandre, Williams, Alan, Depil, Stéphane, Duchateau, Philippe, Poirot, Laurent, Valton, Julien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853973/
https://www.ncbi.nlm.nih.gov/pubmed/31723132
http://dx.doi.org/10.1038/s41467-019-13088-3
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author Sachdeva, Mohit
Busser, Brian W.
Temburni, Sonal
Jahangiri, Billal
Gautron, Anne-Sophie
Maréchal, Alan
Juillerat, Alexandre
Williams, Alan
Depil, Stéphane
Duchateau, Philippe
Poirot, Laurent
Valton, Julien
author_facet Sachdeva, Mohit
Busser, Brian W.
Temburni, Sonal
Jahangiri, Billal
Gautron, Anne-Sophie
Maréchal, Alan
Juillerat, Alexandre
Williams, Alan
Depil, Stéphane
Duchateau, Philippe
Poirot, Laurent
Valton, Julien
author_sort Sachdeva, Mohit
collection PubMed
description Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRAC(CAR)), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC(CAR) T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner.
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spelling pubmed-68539732019-11-18 Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality Sachdeva, Mohit Busser, Brian W. Temburni, Sonal Jahangiri, Billal Gautron, Anne-Sophie Maréchal, Alan Juillerat, Alexandre Williams, Alan Depil, Stéphane Duchateau, Philippe Poirot, Laurent Valton, Julien Nat Commun Article Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRAC(CAR)), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC(CAR) T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner. Nature Publishing Group UK 2019-11-13 /pmc/articles/PMC6853973/ /pubmed/31723132 http://dx.doi.org/10.1038/s41467-019-13088-3 Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sachdeva, Mohit
Busser, Brian W.
Temburni, Sonal
Jahangiri, Billal
Gautron, Anne-Sophie
Maréchal, Alan
Juillerat, Alexandre
Williams, Alan
Depil, Stéphane
Duchateau, Philippe
Poirot, Laurent
Valton, Julien
Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
title Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
title_full Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
title_fullStr Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
title_full_unstemmed Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
title_short Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
title_sort repurposing endogenous immune pathways to tailor and control chimeric antigen receptor t cell functionality
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853973/
https://www.ncbi.nlm.nih.gov/pubmed/31723132
http://dx.doi.org/10.1038/s41467-019-13088-3
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