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Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition

Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the...

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Autores principales: Condomines, Maud, Arnason, Jon, Benjamin, Reuben, Gunset, Gertrude, Plotkin, Jason, Sadelain, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482147/
https://www.ncbi.nlm.nih.gov/pubmed/26110267
http://dx.doi.org/10.1371/journal.pone.0130518
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author Condomines, Maud
Arnason, Jon
Benjamin, Reuben
Gunset, Gertrude
Plotkin, Jason
Sadelain, Michel
author_facet Condomines, Maud
Arnason, Jon
Benjamin, Reuben
Gunset, Gertrude
Plotkin, Jason
Sadelain, Michel
author_sort Condomines, Maud
collection PubMed
description Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z(+) T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1(+) or 19z1-CD80(+) T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z(+) T cells had 10-fold reduced tumor progression compared to those treated with 19z1(+) or 19z1-CD80(+) T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80(+) T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z(+) T cells. Our results establish that CTLA-4 down-regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function.
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spelling pubmed-44821472015-07-01 Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition Condomines, Maud Arnason, Jon Benjamin, Reuben Gunset, Gertrude Plotkin, Jason Sadelain, Michel PLoS One Research Article Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z(+) T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1(+) or 19z1-CD80(+) T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z(+) T cells had 10-fold reduced tumor progression compared to those treated with 19z1(+) or 19z1-CD80(+) T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80(+) T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z(+) T cells. Our results establish that CTLA-4 down-regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function. Public Library of Science 2015-06-25 /pmc/articles/PMC4482147/ /pubmed/26110267 http://dx.doi.org/10.1371/journal.pone.0130518 Text en © 2015 Condomines et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Condomines, Maud
Arnason, Jon
Benjamin, Reuben
Gunset, Gertrude
Plotkin, Jason
Sadelain, Michel
Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition
title Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition
title_full Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition
title_fullStr Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition
title_full_unstemmed Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition
title_short Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition
title_sort tumor-targeted human t cells expressing cd28-based chimeric antigen receptors circumvent ctla-4 inhibition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482147/
https://www.ncbi.nlm.nih.gov/pubmed/26110267
http://dx.doi.org/10.1371/journal.pone.0130518
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