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2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies

BACKGROUND: Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T c...

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Autores principales: Xu, Yingxi, Liu, Qian, Zhong, Mengjun, Wang, Zhenzhen, Chen, Zhaoqi, Zhang, Yu, Xing, Haiyan, Tian, Zheng, Tang, Kejing, Liao, Xiaolong, Rao, Qing, Wang, Min, Wang, Jianxiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524286/
https://www.ncbi.nlm.nih.gov/pubmed/31097020
http://dx.doi.org/10.1186/s13045-019-0732-7
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author Xu, Yingxi
Liu, Qian
Zhong, Mengjun
Wang, Zhenzhen
Chen, Zhaoqi
Zhang, Yu
Xing, Haiyan
Tian, Zheng
Tang, Kejing
Liao, Xiaolong
Rao, Qing
Wang, Min
Wang, Jianxiang
author_facet Xu, Yingxi
Liu, Qian
Zhong, Mengjun
Wang, Zhenzhen
Chen, Zhaoqi
Zhang, Yu
Xing, Haiyan
Tian, Zheng
Tang, Kejing
Liao, Xiaolong
Rao, Qing
Wang, Min
Wang, Jianxiang
author_sort Xu, Yingxi
collection PubMed
description BACKGROUND: Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T cell malignancies using CAR-T cells remains limited due to the shared antigens between malignant T cells and normal T cells. CD5 is considered one of the important characteristic markers of malignant T cells and is expressed on almost all normal T cells but not on NK-92 cells. Recently, NK-92 cells have been utilized as CAR-modified immune cells. However, in preclinical models, CAR-T cells seem to be superior to CAR-NK-92 cells. Therefore, we speculate that in addition to the short lifespan of NK-92 cells in mice, the costimulatory domain used in CAR constructs might not be suitable for CAR-NK-92 cell engineering. METHODS: Two second-generation anti-CD5 CAR plasmids with different costimulatory domains were constructed, one using the T-cell-associated activating receptor-4-1BB (BB.z) and the other using a NK-cell-associated activating receptor-2B4 (2B4.z). Subsequently, BB.z-NK and 2B4.z-NK were generated. Specific cytotoxicity against CD5(+) malignant cell lines, primary CD5(+) malignant cells, and normal T cells was evaluated in vitro. Moreover, a CD5(+) T cell acute lymphoblastic leukemia (T-ALL) mouse model was established and used to assess the efficacy of CD5-CAR NK immunotherapy in vivo. RESULTS: Both BB.z-NK and 2B4.z-NK exhibited specific cytotoxicity against CD5(+) malignant cells in vitro and prolonged the survival of T-ALL xenograft mice. Encouragingly, 2B4.z-NK cells displayed greater anti-CD5(+) malignancy capacity than that of BB.z-NK, accompanied by a greater direct lytic side effect versus BB.z-NK. CONCLUSIONS: Anti-CD5 CAR-NK cells, particularly those constructed with the intracellular domain of NK-cell-associated activating receptor 2B4, may be a promising strategy for T cell malignancy treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-019-0732-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-65242862019-05-24 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies Xu, Yingxi Liu, Qian Zhong, Mengjun Wang, Zhenzhen Chen, Zhaoqi Zhang, Yu Xing, Haiyan Tian, Zheng Tang, Kejing Liao, Xiaolong Rao, Qing Wang, Min Wang, Jianxiang J Hematol Oncol Research BACKGROUND: Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T cell malignancies using CAR-T cells remains limited due to the shared antigens between malignant T cells and normal T cells. CD5 is considered one of the important characteristic markers of malignant T cells and is expressed on almost all normal T cells but not on NK-92 cells. Recently, NK-92 cells have been utilized as CAR-modified immune cells. However, in preclinical models, CAR-T cells seem to be superior to CAR-NK-92 cells. Therefore, we speculate that in addition to the short lifespan of NK-92 cells in mice, the costimulatory domain used in CAR constructs might not be suitable for CAR-NK-92 cell engineering. METHODS: Two second-generation anti-CD5 CAR plasmids with different costimulatory domains were constructed, one using the T-cell-associated activating receptor-4-1BB (BB.z) and the other using a NK-cell-associated activating receptor-2B4 (2B4.z). Subsequently, BB.z-NK and 2B4.z-NK were generated. Specific cytotoxicity against CD5(+) malignant cell lines, primary CD5(+) malignant cells, and normal T cells was evaluated in vitro. Moreover, a CD5(+) T cell acute lymphoblastic leukemia (T-ALL) mouse model was established and used to assess the efficacy of CD5-CAR NK immunotherapy in vivo. RESULTS: Both BB.z-NK and 2B4.z-NK exhibited specific cytotoxicity against CD5(+) malignant cells in vitro and prolonged the survival of T-ALL xenograft mice. Encouragingly, 2B4.z-NK cells displayed greater anti-CD5(+) malignancy capacity than that of BB.z-NK, accompanied by a greater direct lytic side effect versus BB.z-NK. CONCLUSIONS: Anti-CD5 CAR-NK cells, particularly those constructed with the intracellular domain of NK-cell-associated activating receptor 2B4, may be a promising strategy for T cell malignancy treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-019-0732-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-16 /pmc/articles/PMC6524286/ /pubmed/31097020 http://dx.doi.org/10.1186/s13045-019-0732-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Xu, Yingxi
Liu, Qian
Zhong, Mengjun
Wang, Zhenzhen
Chen, Zhaoqi
Zhang, Yu
Xing, Haiyan
Tian, Zheng
Tang, Kejing
Liao, Xiaolong
Rao, Qing
Wang, Min
Wang, Jianxiang
2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
title 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
title_full 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
title_fullStr 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
title_full_unstemmed 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
title_short 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
title_sort 2b4 costimulatory domain enhancing cytotoxic ability of anti-cd5 chimeric antigen receptor engineered natural killer cells against t cell malignancies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524286/
https://www.ncbi.nlm.nih.gov/pubmed/31097020
http://dx.doi.org/10.1186/s13045-019-0732-7
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