Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro

Adoptive cell therapy (ACT) based on TCR- or CAR-T cells has become an efficient immunotherapeutic approach for the treatment of various diseases, including cancer. Previously, we developed a novel strategy for generating therapeutic T cell products based on chain-centric TCRs, in which either α- or...

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Autores principales:	Anastasiia Kalinina, Alexandra Bruter, Nadezhda Persiyantseva, Yulia Silaeva, Maria Zamkova, Ludmila Khromykh, Dmitry Kazansky
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Adoptive cell therapy Chain-centric TCR T cell product Toxicity Preclinical study Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/9a07af43c47d43499f688336181fc705
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spelling	oai:doaj.org-article:9a07af43c47d43499f688336181fc7052021-12-04T04:33:06ZSafety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro0753-332210.1016/j.biopha.2021.112480https://doaj.org/article/9a07af43c47d43499f688336181fc7052022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S075333222101266Xhttps://doaj.org/toc/0753-3322Adoptive cell therapy (ACT) based on TCR- or CAR-T cells has become an efficient immunotherapeutic approach for the treatment of various diseases, including cancer. Previously, we developed a novel strategy for generating therapeutic T cell products based on chain-centric TCRs, in which either α- or β-chain dominates in cognate antigen recognition. To assess the suitability of our experimental approach for the clinical application and predict its possible adverse effects, in studies here, we evaluated the safety of the experimental TCRα-modified T cell product in mouse preclinical models. Our data showed no tumorigenic or mutagenic activity in vitro of TCRα-transduced T cells, indicating no genotoxicity of viral vectors used for the generation of the experimental T cell product. Adoptive transfer of TCRα-engineered T cells in a wide dose range didn`t disturb the host homeostasis and exhibited no acute toxicity or immunotoxicity in vivo. Based on pharmacokinetics and pharmacodynamics analysis here, modified T cells rapidly penetrated and distributed in many viscera after infusion. Histological evaluations revealed no pathological changes in organs caused by T cells accumulation, indicating the absence of non-specific off-target activity or cross-reactivity of the therapeutic TCRα. Studies here provide valuable information on the potential safety of TCRα-T cell based ACT that could be extrapolated to possible effects in a human host.Anastasiia KalininaAlexandra BruterNadezhda PersiyantsevaYulia SilaevaMaria ZamkovaLudmila KhromykhDmitry KazanskyElsevierarticleAdoptive cell therapyChain-centric TCRT cell productToxicityPreclinical studyTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112480- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Adoptive cell therapy Chain-centric TCR T cell product Toxicity Preclinical study Therapeutics. Pharmacology RM1-950
spellingShingle	Adoptive cell therapy Chain-centric TCR T cell product Toxicity Preclinical study Therapeutics. Pharmacology RM1-950 Anastasiia Kalinina Alexandra Bruter Nadezhda Persiyantseva Yulia Silaeva Maria Zamkova Ludmila Khromykh Dmitry Kazansky Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro
description	Adoptive cell therapy (ACT) based on TCR- or CAR-T cells has become an efficient immunotherapeutic approach for the treatment of various diseases, including cancer. Previously, we developed a novel strategy for generating therapeutic T cell products based on chain-centric TCRs, in which either α- or β-chain dominates in cognate antigen recognition. To assess the suitability of our experimental approach for the clinical application and predict its possible adverse effects, in studies here, we evaluated the safety of the experimental TCRα-modified T cell product in mouse preclinical models. Our data showed no tumorigenic or mutagenic activity in vitro of TCRα-transduced T cells, indicating no genotoxicity of viral vectors used for the generation of the experimental T cell product. Adoptive transfer of TCRα-engineered T cells in a wide dose range didn`t disturb the host homeostasis and exhibited no acute toxicity or immunotoxicity in vivo. Based on pharmacokinetics and pharmacodynamics analysis here, modified T cells rapidly penetrated and distributed in many viscera after infusion. Histological evaluations revealed no pathological changes in organs caused by T cells accumulation, indicating the absence of non-specific off-target activity or cross-reactivity of the therapeutic TCRα. Studies here provide valuable information on the potential safety of TCRα-T cell based ACT that could be extrapolated to possible effects in a human host.
format	article
author	Anastasiia Kalinina Alexandra Bruter Nadezhda Persiyantseva Yulia Silaeva Maria Zamkova Ludmila Khromykh Dmitry Kazansky
author_facet	Anastasiia Kalinina Alexandra Bruter Nadezhda Persiyantseva Yulia Silaeva Maria Zamkova Ludmila Khromykh Dmitry Kazansky
author_sort	Anastasiia Kalinina
title	Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro
title_short	Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro
title_full	Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro
title_fullStr	Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro
title_full_unstemmed	Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro
title_sort	safety evaluation of the mouse tcrα - transduced t cell product in preclinical models in vivo and in vitro
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/9a07af43c47d43499f688336181fc705
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Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro

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