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Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies

Chimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. I...

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Autores principales: Yoo, Hyeon Joo, Liu, Yibin, Wang, Lei, Schubert, Maria-Luisa, Hoffmann, Jean-Marc, Wang, Sanmei, Neuber, Brigitte, Hückelhoven-Krauss, Angela, Gern, Ulrike, Schmitt, Anita, Müller-Tidow, Carsten, Dreger, Peter, Mokhir, Andriy, Schmitt, Michael, Sellner, Leopold
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566309/
https://www.ncbi.nlm.nih.gov/pubmed/31109083
http://dx.doi.org/10.3390/ijms20102469
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author Yoo, Hyeon Joo
Liu, Yibin
Wang, Lei
Schubert, Maria-Luisa
Hoffmann, Jean-Marc
Wang, Sanmei
Neuber, Brigitte
Hückelhoven-Krauss, Angela
Gern, Ulrike
Schmitt, Anita
Müller-Tidow, Carsten
Dreger, Peter
Mokhir, Andriy
Schmitt, Michael
Sellner, Leopold
author_facet Yoo, Hyeon Joo
Liu, Yibin
Wang, Lei
Schubert, Maria-Luisa
Hoffmann, Jean-Marc
Wang, Sanmei
Neuber, Brigitte
Hückelhoven-Krauss, Angela
Gern, Ulrike
Schmitt, Anita
Müller-Tidow, Carsten
Dreger, Peter
Mokhir, Andriy
Schmitt, Michael
Sellner, Leopold
author_sort Yoo, Hyeon Joo
collection PubMed
description Chimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. In this study, we aimed to exploit increased ROS levels in the tumor microenvironment with prodrugs of ROS accelerators, which are specifically activated in cancer cells. Upon activation, ROS accelerators induce further generation of ROS. This leads to an accumulation of ROS in tumor cells. We hypothesized that the latter cells will be more susceptible to CARTs. CD19-specific CARTs were generated with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Cytotoxicity was determined by chromium-51 release assay. Influence of the ROS accelerators on viability and phenotype of CARTs was determined by flow cytometry. The combination of CARTs with the ROS accelerator PipFcB significantly increased their cytotoxicity in the Burkitt lymphoma cell lines Raji and Daudi, as well as primary chronic lymphocytic leukemia cells. Exposure of CARTs to PipFcB for 48 h did not influence T cell exhaustion, viability, or T cell subpopulations. In summary, the combination of CARTs with ROS accelerators may improve adoptive immunotherapy and help to overcome tumor microenvironment-mediated treatment resistance.
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spelling pubmed-65663092019-06-17 Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies Yoo, Hyeon Joo Liu, Yibin Wang, Lei Schubert, Maria-Luisa Hoffmann, Jean-Marc Wang, Sanmei Neuber, Brigitte Hückelhoven-Krauss, Angela Gern, Ulrike Schmitt, Anita Müller-Tidow, Carsten Dreger, Peter Mokhir, Andriy Schmitt, Michael Sellner, Leopold Int J Mol Sci Article Chimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. In this study, we aimed to exploit increased ROS levels in the tumor microenvironment with prodrugs of ROS accelerators, which are specifically activated in cancer cells. Upon activation, ROS accelerators induce further generation of ROS. This leads to an accumulation of ROS in tumor cells. We hypothesized that the latter cells will be more susceptible to CARTs. CD19-specific CARTs were generated with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Cytotoxicity was determined by chromium-51 release assay. Influence of the ROS accelerators on viability and phenotype of CARTs was determined by flow cytometry. The combination of CARTs with the ROS accelerator PipFcB significantly increased their cytotoxicity in the Burkitt lymphoma cell lines Raji and Daudi, as well as primary chronic lymphocytic leukemia cells. Exposure of CARTs to PipFcB for 48 h did not influence T cell exhaustion, viability, or T cell subpopulations. In summary, the combination of CARTs with ROS accelerators may improve adoptive immunotherapy and help to overcome tumor microenvironment-mediated treatment resistance. MDPI 2019-05-18 /pmc/articles/PMC6566309/ /pubmed/31109083 http://dx.doi.org/10.3390/ijms20102469 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yoo, Hyeon Joo
Liu, Yibin
Wang, Lei
Schubert, Maria-Luisa
Hoffmann, Jean-Marc
Wang, Sanmei
Neuber, Brigitte
Hückelhoven-Krauss, Angela
Gern, Ulrike
Schmitt, Anita
Müller-Tidow, Carsten
Dreger, Peter
Mokhir, Andriy
Schmitt, Michael
Sellner, Leopold
Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
title Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
title_full Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
title_fullStr Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
title_full_unstemmed Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
title_short Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
title_sort tumor-specific reactive oxygen species accelerators improve chimeric antigen receptor t cell therapy in b cell malignancies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566309/
https://www.ncbi.nlm.nih.gov/pubmed/31109083
http://dx.doi.org/10.3390/ijms20102469
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