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Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in B cell malignancies. However, high tumor burden limits clinical efficacy and increases the risk of cytokine release syndrome and neurotoxicity, which is associated with over-activation of the CAR-T...

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Autores principales: Zhang, Ang, Sun, Yao, Du, Jie, Dong, Yansheng, Pang, Honggang, Ma, Lei, Si, Shaoyan, Zhang, Zhong, He, Mingyi, Yue, Yang, Zhang, Xiaoli, Zhao, Weichao, Pi, Jianjun, Chang, Mindong, Wang, Quanjun, Zhang, Yikun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524077/
https://www.ncbi.nlm.nih.gov/pubmed/34675920
http://dx.doi.org/10.3389/fimmu.2021.724211
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author Zhang, Ang
Sun, Yao
Du, Jie
Dong, Yansheng
Pang, Honggang
Ma, Lei
Si, Shaoyan
Zhang, Zhong
He, Mingyi
Yue, Yang
Zhang, Xiaoli
Zhao, Weichao
Pi, Jianjun
Chang, Mindong
Wang, Quanjun
Zhang, Yikun
author_facet Zhang, Ang
Sun, Yao
Du, Jie
Dong, Yansheng
Pang, Honggang
Ma, Lei
Si, Shaoyan
Zhang, Zhong
He, Mingyi
Yue, Yang
Zhang, Xiaoli
Zhao, Weichao
Pi, Jianjun
Chang, Mindong
Wang, Quanjun
Zhang, Yikun
author_sort Zhang, Ang
collection PubMed
description Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in B cell malignancies. However, high tumor burden limits clinical efficacy and increases the risk of cytokine release syndrome and neurotoxicity, which is associated with over-activation of the CAR-T cells. The hinge domain plays an important role in the function of CAR-T cells. We hypothesized that deletion of glycine, an amino acid with good flexibility, may reduce the flexibility of the hinge region, thereby mitigating CAR-T cell over-activation. This study involved generating a novel CAR by deletion of two consecutive glycine residues in the CD8 hinge domain of second-generation (2nd) CAR, thereafter named 2nd-GG CAR. The 2nd-GG CAR-T cells showed similar efficacy of CAR expression but lower hinge flexibility, and its protein affinity to CD19 protein was lower than that of 2nd CAR-T cells. Compared to the 2nd CAR-T cells, 2nd-GG CAR-T cells reduced proinflammatory cytokine secretion without diminishing the specific cytotoxicity toward tumor cells in vitro. Furthermore, 2nd-GG CAR-T cells prolonged overall survival in an immunodeficient mouse model bearing NALM-6 when tumor burden was high. This study demonstrated that a lower-flexibility of CD8α hinge improved survival under high tumor burden and reduced proinflammatory cytokines in preclinical studies. While there is potential for improved safety and efficacy, yet this needs validation with clinical trials.
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spelling pubmed-85240772021-10-20 Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release Zhang, Ang Sun, Yao Du, Jie Dong, Yansheng Pang, Honggang Ma, Lei Si, Shaoyan Zhang, Zhong He, Mingyi Yue, Yang Zhang, Xiaoli Zhao, Weichao Pi, Jianjun Chang, Mindong Wang, Quanjun Zhang, Yikun Front Immunol Immunology Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in B cell malignancies. However, high tumor burden limits clinical efficacy and increases the risk of cytokine release syndrome and neurotoxicity, which is associated with over-activation of the CAR-T cells. The hinge domain plays an important role in the function of CAR-T cells. We hypothesized that deletion of glycine, an amino acid with good flexibility, may reduce the flexibility of the hinge region, thereby mitigating CAR-T cell over-activation. This study involved generating a novel CAR by deletion of two consecutive glycine residues in the CD8 hinge domain of second-generation (2nd) CAR, thereafter named 2nd-GG CAR. The 2nd-GG CAR-T cells showed similar efficacy of CAR expression but lower hinge flexibility, and its protein affinity to CD19 protein was lower than that of 2nd CAR-T cells. Compared to the 2nd CAR-T cells, 2nd-GG CAR-T cells reduced proinflammatory cytokine secretion without diminishing the specific cytotoxicity toward tumor cells in vitro. Furthermore, 2nd-GG CAR-T cells prolonged overall survival in an immunodeficient mouse model bearing NALM-6 when tumor burden was high. This study demonstrated that a lower-flexibility of CD8α hinge improved survival under high tumor burden and reduced proinflammatory cytokines in preclinical studies. While there is potential for improved safety and efficacy, yet this needs validation with clinical trials. Frontiers Media S.A. 2021-10-05 /pmc/articles/PMC8524077/ /pubmed/34675920 http://dx.doi.org/10.3389/fimmu.2021.724211 Text en Copyright © 2021 Zhang, Sun, Du, Dong, Pang, Ma, Si, Zhang, He, Yue, Zhang, Zhao, Pi, Chang, Wang and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhang, Ang
Sun, Yao
Du, Jie
Dong, Yansheng
Pang, Honggang
Ma, Lei
Si, Shaoyan
Zhang, Zhong
He, Mingyi
Yue, Yang
Zhang, Xiaoli
Zhao, Weichao
Pi, Jianjun
Chang, Mindong
Wang, Quanjun
Zhang, Yikun
Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release
title Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release
title_full Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release
title_fullStr Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release
title_full_unstemmed Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release
title_short Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release
title_sort reducing hinge flexibility of car-t cells prolongs survival in vivo with low cytokines release
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524077/
https://www.ncbi.nlm.nih.gov/pubmed/34675920
http://dx.doi.org/10.3389/fimmu.2021.724211
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