Cargando…
Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation
A primary goal in transplantation medicine is the induction of a tolerogenic environment for prevention of transplant rejection without the need for long-term pharmacological immunosuppression. Generation of alloantigen-specific regulatory T cells (Tregs) by transduction with chimeric antigen recept...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113151/ https://www.ncbi.nlm.nih.gov/pubmed/35931871 http://dx.doi.org/10.1038/s41434-022-00358-x |
_version_ | 1785027775926632448 |
---|---|
author | Proics, Emma David, Marion Mojibian, Majid Speck, Madeline Lounnas-Mourey, Nadia Govehovitch, Adeline Baghdadi, Wissam Desnouveaux, Justine Bastian, Hervé Freschi, Laura Privat, Geoffrey Pouzet, Cédric Grossi, Mauro Heimendinger, Pierre Abel, Tobias Fenard, David Levings, Megan K. Meyer, François Dumont, Céline |
author_facet | Proics, Emma David, Marion Mojibian, Majid Speck, Madeline Lounnas-Mourey, Nadia Govehovitch, Adeline Baghdadi, Wissam Desnouveaux, Justine Bastian, Hervé Freschi, Laura Privat, Geoffrey Pouzet, Cédric Grossi, Mauro Heimendinger, Pierre Abel, Tobias Fenard, David Levings, Megan K. Meyer, François Dumont, Céline |
author_sort | Proics, Emma |
collection | PubMed |
description | A primary goal in transplantation medicine is the induction of a tolerogenic environment for prevention of transplant rejection without the need for long-term pharmacological immunosuppression. Generation of alloantigen-specific regulatory T cells (Tregs) by transduction with chimeric antigen receptors (CARs) is a promising strategy to achieve this goal. This publication reports the preclinical characterization of Tregs (TR101) transduced with a human leukocyte antigen (HLA)-A*02 CAR lentiviral vector (TX200) designated to induce immunosuppression of allograft-specific effector T cells in HLA-A*02-negative recipients of HLA-A*02-positive transplants. In vitro results demonstrated specificity, immunosuppressive function, and safety of TX200-TR101. In NOD scid gamma (NSG) mice, TX200-TR101 prevented graft-versus-host disease (GvHD) in a xenogeneic GvHD model and TX200-TR101 Tregs localized to human HLA-A*02-positive skin transplants in a transplant model. TX200-TR101 persisted over the entire duration of a 3-month study in humanized HLA-A*02 NSG mice and remained stable, without switching to a proinflammatory phenotype. Concomitant tacrolimus did not impair TX200-TR101 Treg survival or their ability to inhibit peripheral blood mononuclear cell (PBMC) engraftment. These data demonstrate that TX200-TR101 is specific, stable, efficacious, and safe in preclinical models, and provide the basis for a first-in-human study. |
format | Online Article Text |
id | pubmed-10113151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101131512023-04-20 Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation Proics, Emma David, Marion Mojibian, Majid Speck, Madeline Lounnas-Mourey, Nadia Govehovitch, Adeline Baghdadi, Wissam Desnouveaux, Justine Bastian, Hervé Freschi, Laura Privat, Geoffrey Pouzet, Cédric Grossi, Mauro Heimendinger, Pierre Abel, Tobias Fenard, David Levings, Megan K. Meyer, François Dumont, Céline Gene Ther Article A primary goal in transplantation medicine is the induction of a tolerogenic environment for prevention of transplant rejection without the need for long-term pharmacological immunosuppression. Generation of alloantigen-specific regulatory T cells (Tregs) by transduction with chimeric antigen receptors (CARs) is a promising strategy to achieve this goal. This publication reports the preclinical characterization of Tregs (TR101) transduced with a human leukocyte antigen (HLA)-A*02 CAR lentiviral vector (TX200) designated to induce immunosuppression of allograft-specific effector T cells in HLA-A*02-negative recipients of HLA-A*02-positive transplants. In vitro results demonstrated specificity, immunosuppressive function, and safety of TX200-TR101. In NOD scid gamma (NSG) mice, TX200-TR101 prevented graft-versus-host disease (GvHD) in a xenogeneic GvHD model and TX200-TR101 Tregs localized to human HLA-A*02-positive skin transplants in a transplant model. TX200-TR101 persisted over the entire duration of a 3-month study in humanized HLA-A*02 NSG mice and remained stable, without switching to a proinflammatory phenotype. Concomitant tacrolimus did not impair TX200-TR101 Treg survival or their ability to inhibit peripheral blood mononuclear cell (PBMC) engraftment. These data demonstrate that TX200-TR101 is specific, stable, efficacious, and safe in preclinical models, and provide the basis for a first-in-human study. Nature Publishing Group UK 2022-08-05 2023 /pmc/articles/PMC10113151/ /pubmed/35931871 http://dx.doi.org/10.1038/s41434-022-00358-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Proics, Emma David, Marion Mojibian, Majid Speck, Madeline Lounnas-Mourey, Nadia Govehovitch, Adeline Baghdadi, Wissam Desnouveaux, Justine Bastian, Hervé Freschi, Laura Privat, Geoffrey Pouzet, Cédric Grossi, Mauro Heimendinger, Pierre Abel, Tobias Fenard, David Levings, Megan K. Meyer, François Dumont, Céline Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation |
title | Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation |
title_full | Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation |
title_fullStr | Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation |
title_full_unstemmed | Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation |
title_short | Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation |
title_sort | preclinical assessment of antigen-specific chimeric antigen receptor regulatory t cells for use in solid organ transplantation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113151/ https://www.ncbi.nlm.nih.gov/pubmed/35931871 http://dx.doi.org/10.1038/s41434-022-00358-x |
work_keys_str_mv | AT proicsemma preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT davidmarion preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT mojibianmajid preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT speckmadeline preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT lounnasmoureynadia preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT govehovitchadeline preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT baghdadiwissam preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT desnouveauxjustine preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT bastianherve preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT freschilaura preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT privatgeoffrey preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT pouzetcedric preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT grossimauro preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT heimendingerpierre preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT abeltobias preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT fenarddavid preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT levingsmegank preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT meyerfrancois preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation AT dumontceline preclinicalassessmentofantigenspecificchimericantigenreceptorregulatorytcellsforuseinsolidorgantransplantation |