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Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells
BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown considerable promise as a personalized cellular immunotherapy against B cell malignancies. However, the complex and lengthy manufacturing processes involved in generating CAR T cell products ex vivo result in substantial production time...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438880/ https://www.ncbi.nlm.nih.gov/pubmed/34518288 http://dx.doi.org/10.1136/jitc-2021-002737 |
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author | Huckaby, Justin T Landoni, Elisa Jacobs, Timothy M Savoldo, Barbara Dotti, Gianpietro Lai, Samuel K |
author_facet | Huckaby, Justin T Landoni, Elisa Jacobs, Timothy M Savoldo, Barbara Dotti, Gianpietro Lai, Samuel K |
author_sort | Huckaby, Justin T |
collection | PubMed |
description | BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown considerable promise as a personalized cellular immunotherapy against B cell malignancies. However, the complex and lengthy manufacturing processes involved in generating CAR T cell products ex vivo result in substantial production time delays and high costs. Furthermore, ex vivo expansion of T cells promotes cell differentiation that reduces their in vivo replicative capacity and longevity. METHODS: Here, to overcome these limitations, CAR-T cells are engineered directly in vivo by administering a lentivirus expressing a mutant Sindbis envelope, coupled with a bispecific antibody binder that redirects the virus to CD3(+) human T cells. RESULTS: This redirected lentiviral system offers exceptional specificity and efficiency; a single dose of the virus delivered to immunodeficient mice engrafted with human peripheral blood mononuclear cells generates CD19-specific CAR-T cells that markedly control the growth of an aggressive pre-established xenograft B cell tumor. CONCLUSIONS: These findings underscore in vivo engineering of CAR-T cells as a promising approach for personalized cancer immunotherapy. |
format | Online Article Text |
id | pubmed-8438880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-84388802021-09-24 Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells Huckaby, Justin T Landoni, Elisa Jacobs, Timothy M Savoldo, Barbara Dotti, Gianpietro Lai, Samuel K J Immunother Cancer Immune Cell Therapies and Immune Cell Engineering BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown considerable promise as a personalized cellular immunotherapy against B cell malignancies. However, the complex and lengthy manufacturing processes involved in generating CAR T cell products ex vivo result in substantial production time delays and high costs. Furthermore, ex vivo expansion of T cells promotes cell differentiation that reduces their in vivo replicative capacity and longevity. METHODS: Here, to overcome these limitations, CAR-T cells are engineered directly in vivo by administering a lentivirus expressing a mutant Sindbis envelope, coupled with a bispecific antibody binder that redirects the virus to CD3(+) human T cells. RESULTS: This redirected lentiviral system offers exceptional specificity and efficiency; a single dose of the virus delivered to immunodeficient mice engrafted with human peripheral blood mononuclear cells generates CD19-specific CAR-T cells that markedly control the growth of an aggressive pre-established xenograft B cell tumor. CONCLUSIONS: These findings underscore in vivo engineering of CAR-T cells as a promising approach for personalized cancer immunotherapy. BMJ Publishing Group 2021-09-12 /pmc/articles/PMC8438880/ /pubmed/34518288 http://dx.doi.org/10.1136/jitc-2021-002737 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Immune Cell Therapies and Immune Cell Engineering Huckaby, Justin T Landoni, Elisa Jacobs, Timothy M Savoldo, Barbara Dotti, Gianpietro Lai, Samuel K Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells |
title | Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells |
title_full | Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells |
title_fullStr | Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells |
title_full_unstemmed | Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells |
title_short | Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells |
title_sort | bispecific binder redirected lentiviral vector enables in vivo engineering of car-t cells |
topic | Immune Cell Therapies and Immune Cell Engineering |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438880/ https://www.ncbi.nlm.nih.gov/pubmed/34518288 http://dx.doi.org/10.1136/jitc-2021-002737 |
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