Cargando…
Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory
Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address thes...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243241/ https://www.ncbi.nlm.nih.gov/pubmed/30373813 http://dx.doi.org/10.1073/pnas.1810060115 |
_version_ | 1783371944306933760 |
---|---|
author | Viaud, Sophie Ma, Jennifer S. Y. Hardy, Ian R. Hampton, Eric N. Benish, Brent Sherwood, Lance Nunez, Vanessa Ackerman, Christopher J. Khialeeva, Elvira Weglarz, Meredith Lee, Sung Chang Woods, Ashley K. Young, Travis S. |
author_facet | Viaud, Sophie Ma, Jennifer S. Y. Hardy, Ian R. Hampton, Eric N. Benish, Brent Sherwood, Lance Nunez, Vanessa Ackerman, Christopher J. Khialeeva, Elvira Weglarz, Meredith Lee, Sung Chang Woods, Ashley K. Young, Travis S. |
author_sort | Viaud, Sophie |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the “rest” period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products. |
format | Online Article Text |
id | pubmed-6243241 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-62432412018-11-27 Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory Viaud, Sophie Ma, Jennifer S. Y. Hardy, Ian R. Hampton, Eric N. Benish, Brent Sherwood, Lance Nunez, Vanessa Ackerman, Christopher J. Khialeeva, Elvira Weglarz, Meredith Lee, Sung Chang Woods, Ashley K. Young, Travis S. Proc Natl Acad Sci U S A PNAS Plus Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the “rest” period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products. National Academy of Sciences 2018-11-13 2018-10-29 /pmc/articles/PMC6243241/ /pubmed/30373813 http://dx.doi.org/10.1073/pnas.1810060115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | PNAS Plus Viaud, Sophie Ma, Jennifer S. Y. Hardy, Ian R. Hampton, Eric N. Benish, Brent Sherwood, Lance Nunez, Vanessa Ackerman, Christopher J. Khialeeva, Elvira Weglarz, Meredith Lee, Sung Chang Woods, Ashley K. Young, Travis S. Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
title | Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
title_full | Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
title_fullStr | Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
title_full_unstemmed | Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
title_short | Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
title_sort | switchable control over in vivo car t expansion, b cell depletion, and induction of memory |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243241/ https://www.ncbi.nlm.nih.gov/pubmed/30373813 http://dx.doi.org/10.1073/pnas.1810060115 |
work_keys_str_mv | AT viaudsophie switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT majennifersy switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT hardyianr switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT hamptonericn switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT benishbrent switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT sherwoodlance switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT nunezvanessa switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT ackermanchristopherj switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT khialeevaelvira switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT weglarzmeredith switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT leesungchang switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT woodsashleyk switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory AT youngtraviss switchablecontroloverinvivocartexpansionbcelldepletionandinductionofmemory |