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Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo

Although chimeric antigen receptor T (CAR-T) cell therapy achieves high remission rates, challenges (e.g., toxicity management and relapse prevention) remain. The major risks are cytokine release syndrome and related neurological toxicity. The influence of the CAR surface density on the efficacy/saf...

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Autores principales: Ho, Jin-Yuan, Wang, Lin, Liu, Ying, Ba, Min, Yang, Junfang, Zhang, Xian, Chen, Dandan, Lu, Peihua, Li, Jianqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027690/
https://www.ncbi.nlm.nih.gov/pubmed/33869653
http://dx.doi.org/10.1016/j.omtm.2021.03.007
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author Ho, Jin-Yuan
Wang, Lin
Liu, Ying
Ba, Min
Yang, Junfang
Zhang, Xian
Chen, Dandan
Lu, Peihua
Li, Jianqiang
author_facet Ho, Jin-Yuan
Wang, Lin
Liu, Ying
Ba, Min
Yang, Junfang
Zhang, Xian
Chen, Dandan
Lu, Peihua
Li, Jianqiang
author_sort Ho, Jin-Yuan
collection PubMed
description Although chimeric antigen receptor T (CAR-T) cell therapy achieves high remission rates, challenges (e.g., toxicity management and relapse prevention) remain. The major risks are cytokine release syndrome and related neurological toxicity. The influence of the CAR surface density on the efficacy/safety of CAR-T cell therapy and the factors determining CAR density were not elucidated comprehensively. Here, we discovered that the use of the MND promoter increased the transduction rate and reduced the CAR surface density. Additionally, MND-driven CAR-T cells had prolonged antileukemia activity in a mouse model. In an initial dual-armed anti-CD19 CAR-T cell pilot study (ClinicalTrials.gov: NCT03840317), eight and six subjects were infused with MND and EF1α promoter-driven autologous CAR-T cells (3 × 10(5) CAR-T cells/kg), respectively. MND subjects developed mild fever and lower interferon gamma (IFN-γ) concentrations than in the EF1A19 group. All but one subject in each cohort reached minimal residual disease (MRD)-negative complete remission after the first month of evaluation. These results represent the first comprehensive study on the promoter-driven modulation of CAR-T cell functionality. These findings encourage further evaluation of the potential of the MND promoter to drive CAR-T cells as a broadly applicable cellular product for anticancer immunotherapy.
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spelling pubmed-80276902021-04-16 Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo Ho, Jin-Yuan Wang, Lin Liu, Ying Ba, Min Yang, Junfang Zhang, Xian Chen, Dandan Lu, Peihua Li, Jianqiang Mol Ther Methods Clin Dev Original Article Although chimeric antigen receptor T (CAR-T) cell therapy achieves high remission rates, challenges (e.g., toxicity management and relapse prevention) remain. The major risks are cytokine release syndrome and related neurological toxicity. The influence of the CAR surface density on the efficacy/safety of CAR-T cell therapy and the factors determining CAR density were not elucidated comprehensively. Here, we discovered that the use of the MND promoter increased the transduction rate and reduced the CAR surface density. Additionally, MND-driven CAR-T cells had prolonged antileukemia activity in a mouse model. In an initial dual-armed anti-CD19 CAR-T cell pilot study (ClinicalTrials.gov: NCT03840317), eight and six subjects were infused with MND and EF1α promoter-driven autologous CAR-T cells (3 × 10(5) CAR-T cells/kg), respectively. MND subjects developed mild fever and lower interferon gamma (IFN-γ) concentrations than in the EF1A19 group. All but one subject in each cohort reached minimal residual disease (MRD)-negative complete remission after the first month of evaluation. These results represent the first comprehensive study on the promoter-driven modulation of CAR-T cell functionality. These findings encourage further evaluation of the potential of the MND promoter to drive CAR-T cells as a broadly applicable cellular product for anticancer immunotherapy. American Society of Gene & Cell Therapy 2021-03-13 /pmc/articles/PMC8027690/ /pubmed/33869653 http://dx.doi.org/10.1016/j.omtm.2021.03.007 Text en © 2021 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Ho, Jin-Yuan
Wang, Lin
Liu, Ying
Ba, Min
Yang, Junfang
Zhang, Xian
Chen, Dandan
Lu, Peihua
Li, Jianqiang
Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
title Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
title_full Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
title_fullStr Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
title_full_unstemmed Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
title_short Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
title_sort promoter usage regulating the surface density of car molecules may modulate the kinetics of car-t cells in vivo
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027690/
https://www.ncbi.nlm.nih.gov/pubmed/33869653
http://dx.doi.org/10.1016/j.omtm.2021.03.007
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