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Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma

BACKGROUND: Treatment with chimeric antigen receptor (CAR)-engineered T cells directed against the B-cell maturation antigen (BCMA) promoted transient recovery from multiple myeloma (MM). However, the absence of this antigen on immature plasma cells may limit the efficacy of this modality and facili...

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Autores principales: Kang, Liqing, Zhang, Jian, Li, Minghao, Xu, Nan, Qi, Wei, Tan, Jingwen, Lou, Xiaoyan, Yu, Zhou, Sun, Juanjuan, Wang, Zhenkun, Fu, Chengcheng, Tang, Xiaowen, Dai, Haiping, Chen, Jia, Wu, Depei, Yu, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222432/
https://www.ncbi.nlm.nih.gov/pubmed/32435496
http://dx.doi.org/10.1186/s40364-020-00192-6
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author Kang, Liqing
Zhang, Jian
Li, Minghao
Xu, Nan
Qi, Wei
Tan, Jingwen
Lou, Xiaoyan
Yu, Zhou
Sun, Juanjuan
Wang, Zhenkun
Fu, Chengcheng
Tang, Xiaowen
Dai, Haiping
Chen, Jia
Wu, Depei
Yu, Lei
author_facet Kang, Liqing
Zhang, Jian
Li, Minghao
Xu, Nan
Qi, Wei
Tan, Jingwen
Lou, Xiaoyan
Yu, Zhou
Sun, Juanjuan
Wang, Zhenkun
Fu, Chengcheng
Tang, Xiaowen
Dai, Haiping
Chen, Jia
Wu, Depei
Yu, Lei
author_sort Kang, Liqing
collection PubMed
description BACKGROUND: Treatment with chimeric antigen receptor (CAR)-engineered T cells directed against the B-cell maturation antigen (BCMA) promoted transient recovery from multiple myeloma (MM). However, the absence of this antigen on immature plasma cells may limit the efficacy of this modality and facilitate relapse. The purpose of this study is to characterize a novel CAR that includes both a single-chain variable fragment (scFv)-BCMA and an scFv-CD19 in tandem orientation (tan-CAR) in an attempt to target both BCMA and CD19 expression on MM cells. METHOD: The scFv sequences from the anti-CD19 antibody FMC63 and the anti-BCMA antibody C11D5.3 were ligated in tandem with transmembrane and T-cell signaling domains to generate the tan-CAR construct. Specificity and efficacy of activated tan-CAR T cells were analyzed using in vitro proliferation, cytokine release, and cytolysis assays. We also evaluated the in vivo efficacy with a xenograft mouse model that included target tumor cells that expressed CD19 or BCMA and compared the results to those obtained with conventional CAR T cells. RESULTS: The in vitro studies revealed specific activation of tan-CAR T cells by K562 cells that overexpressed CD19 and/or BCMA. Cell proliferation, cytokine release, and cytolytic activity were all comparable to the responses of single scFv CAR T cells. Importantly, in vivo studies of tan-CAR T cells revealed specific inhibition of tumor growth in the mouse xenograft model that included cells expressing both CD19 and BCMA. Systemic administration of tan-CAR T cells resulted in complete tumor remission, in contrast to the reduced efficacies of BCMA-CAR T and CD19-CAR T alone in this setting. CONCLUSION: We report the successful design and execution of novel tan-CAR T cells that promote significant anti-tumor efficacy against both CD19 and BCMA antigen-positive tumor cells in vitro and in vivo. The data from this study reveal a novel strategy that may help to reduce the rate of relapse in the treatment with single scFv-CAR T cells.
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spelling pubmed-72224322020-05-20 Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma Kang, Liqing Zhang, Jian Li, Minghao Xu, Nan Qi, Wei Tan, Jingwen Lou, Xiaoyan Yu, Zhou Sun, Juanjuan Wang, Zhenkun Fu, Chengcheng Tang, Xiaowen Dai, Haiping Chen, Jia Wu, Depei Yu, Lei Biomark Res Research BACKGROUND: Treatment with chimeric antigen receptor (CAR)-engineered T cells directed against the B-cell maturation antigen (BCMA) promoted transient recovery from multiple myeloma (MM). However, the absence of this antigen on immature plasma cells may limit the efficacy of this modality and facilitate relapse. The purpose of this study is to characterize a novel CAR that includes both a single-chain variable fragment (scFv)-BCMA and an scFv-CD19 in tandem orientation (tan-CAR) in an attempt to target both BCMA and CD19 expression on MM cells. METHOD: The scFv sequences from the anti-CD19 antibody FMC63 and the anti-BCMA antibody C11D5.3 were ligated in tandem with transmembrane and T-cell signaling domains to generate the tan-CAR construct. Specificity and efficacy of activated tan-CAR T cells were analyzed using in vitro proliferation, cytokine release, and cytolysis assays. We also evaluated the in vivo efficacy with a xenograft mouse model that included target tumor cells that expressed CD19 or BCMA and compared the results to those obtained with conventional CAR T cells. RESULTS: The in vitro studies revealed specific activation of tan-CAR T cells by K562 cells that overexpressed CD19 and/or BCMA. Cell proliferation, cytokine release, and cytolytic activity were all comparable to the responses of single scFv CAR T cells. Importantly, in vivo studies of tan-CAR T cells revealed specific inhibition of tumor growth in the mouse xenograft model that included cells expressing both CD19 and BCMA. Systemic administration of tan-CAR T cells resulted in complete tumor remission, in contrast to the reduced efficacies of BCMA-CAR T and CD19-CAR T alone in this setting. CONCLUSION: We report the successful design and execution of novel tan-CAR T cells that promote significant anti-tumor efficacy against both CD19 and BCMA antigen-positive tumor cells in vitro and in vivo. The data from this study reveal a novel strategy that may help to reduce the rate of relapse in the treatment with single scFv-CAR T cells. BioMed Central 2020-05-13 /pmc/articles/PMC7222432/ /pubmed/32435496 http://dx.doi.org/10.1186/s40364-020-00192-6 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.
spellingShingle Research
Kang, Liqing
Zhang, Jian
Li, Minghao
Xu, Nan
Qi, Wei
Tan, Jingwen
Lou, Xiaoyan
Yu, Zhou
Sun, Juanjuan
Wang, Zhenkun
Fu, Chengcheng
Tang, Xiaowen
Dai, Haiping
Chen, Jia
Wu, Depei
Yu, Lei
Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma
title Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma
title_full Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma
title_fullStr Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma
title_full_unstemmed Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma
title_short Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma
title_sort characterization of novel dual tandem cd19/bcma chimeric antigen receptor t cells to potentially treat multiple myeloma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222432/
https://www.ncbi.nlm.nih.gov/pubmed/32435496
http://dx.doi.org/10.1186/s40364-020-00192-6
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