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A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release
The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242878/ https://www.ncbi.nlm.nih.gov/pubmed/30479831 http://dx.doi.org/10.1038/s41421-018-0066-6 |
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author | Xu, Yiyang Yang, Zhiyuan Horan, Lucas H. Zhang, Pengbo Liu, Lianxing Zimdahl, Bryan Green, Shon Lu, Jingwei Morales, Javier F. Barrett, David M. Grupp, Stephan A. Chan, Vivien W. Liu, Hong Liu, Cheng |
author_facet | Xu, Yiyang Yang, Zhiyuan Horan, Lucas H. Zhang, Pengbo Liu, Lianxing Zimdahl, Bryan Green, Shon Lu, Jingwei Morales, Javier F. Barrett, David M. Grupp, Stephan A. Chan, Vivien W. Liu, Hong Liu, Cheng |
author_sort | Xu, Yiyang |
collection | PubMed |
description | The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model. |
format | Online Article Text |
id | pubmed-6242878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62428782018-11-26 A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release Xu, Yiyang Yang, Zhiyuan Horan, Lucas H. Zhang, Pengbo Liu, Lianxing Zimdahl, Bryan Green, Shon Lu, Jingwei Morales, Javier F. Barrett, David M. Grupp, Stephan A. Chan, Vivien W. Liu, Hong Liu, Cheng Cell Discov Article The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model. Nature Publishing Group UK 2018-11-20 /pmc/articles/PMC6242878/ /pubmed/30479831 http://dx.doi.org/10.1038/s41421-018-0066-6 Text en © The Author(s) 2018 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 Xu, Yiyang Yang, Zhiyuan Horan, Lucas H. Zhang, Pengbo Liu, Lianxing Zimdahl, Bryan Green, Shon Lu, Jingwei Morales, Javier F. Barrett, David M. Grupp, Stephan A. Chan, Vivien W. Liu, Hong Liu, Cheng A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release |
title | A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release |
title_full | A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release |
title_fullStr | A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release |
title_full_unstemmed | A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release |
title_short | A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release |
title_sort | novel antibody-tcr (abtcr) platform combines fab-based antigen recognition with gamma/delta-tcr signaling to facilitate t-cell cytotoxicity with low cytokine release |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242878/ https://www.ncbi.nlm.nih.gov/pubmed/30479831 http://dx.doi.org/10.1038/s41421-018-0066-6 |
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