Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction

Abstract Chimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding betw...

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Autores principales:	Alastair Hotblack, Evangelia K. Kokalaki, Morgan J. Palton, Gordon Weng-Kit Cheung, Iwan P. Williams, Somayya Manzoor, Thomas I. Grothier, Alice Piapi, Valeria Fiaccadori, Patrycja Wawrzyniecka, Harriet A. Roddy, Giulia Agliardi, Claire Roddie, Shimobi Onuoha, Simon Thomas, Shaun Cordoba, Martin Pule
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dee4a8da64cb4a34bd085ebded529484
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spelling	oai:doaj.org-article:dee4a8da64cb4a34bd085ebded5294842021-11-14T12:17:14ZTunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction10.1038/s41598-021-01418-92045-2322https://doaj.org/article/dee4a8da64cb4a34bd085ebded5294842021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01418-9https://doaj.org/toc/2045-2322Abstract Chimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding between the tetracycline repressor protein and a small peptide sequence (TIP) to spontaneously assemble as a functional CAR. Addition of the FDA-approved, small molecule antibiotic minocycline, acts as an “off-switch” by displacing the signaling domain and down-tuning CAR T activity. Here we describe the optimization of this split-CAR approach to generate a CAR in which cytotoxicity, cytokine secretion and proliferation can be inhibited in a dose-dependent and reversible manner. Inhibition is effective during on-going CAR T cell activation and inhibits activation and tumor control in vivo. This work shows how optimization of split-CAR structure affects function and adds a novel design allowing easy CAR inhibition through an FDA-approved small molecule.Alastair HotblackEvangelia K. KokalakiMorgan J. PaltonGordon Weng-Kit CheungIwan P. WilliamsSomayya ManzoorThomas I. GrothierAlice PiapiValeria FiaccadoriPatrycja WawrzynieckaHarriet A. RoddyGiulia AgliardiClaire RoddieShimobi OnuohaSimon ThomasShaun CordobaMartin PuleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alastair Hotblack Evangelia K. Kokalaki Morgan J. Palton Gordon Weng-Kit Cheung Iwan P. Williams Somayya Manzoor Thomas I. Grothier Alice Piapi Valeria Fiaccadori Patrycja Wawrzyniecka Harriet A. Roddy Giulia Agliardi Claire Roddie Shimobi Onuoha Simon Thomas Shaun Cordoba Martin Pule Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction
description	Abstract Chimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding between the tetracycline repressor protein and a small peptide sequence (TIP) to spontaneously assemble as a functional CAR. Addition of the FDA-approved, small molecule antibiotic minocycline, acts as an “off-switch” by displacing the signaling domain and down-tuning CAR T activity. Here we describe the optimization of this split-CAR approach to generate a CAR in which cytotoxicity, cytokine secretion and proliferation can be inhibited in a dose-dependent and reversible manner. Inhibition is effective during on-going CAR T cell activation and inhibits activation and tumor control in vivo. This work shows how optimization of split-CAR structure affects function and adds a novel design allowing easy CAR inhibition through an FDA-approved small molecule.
format	article
author	Alastair Hotblack Evangelia K. Kokalaki Morgan J. Palton Gordon Weng-Kit Cheung Iwan P. Williams Somayya Manzoor Thomas I. Grothier Alice Piapi Valeria Fiaccadori Patrycja Wawrzyniecka Harriet A. Roddy Giulia Agliardi Claire Roddie Shimobi Onuoha Simon Thomas Shaun Cordoba Martin Pule
author_facet	Alastair Hotblack Evangelia K. Kokalaki Morgan J. Palton Gordon Weng-Kit Cheung Iwan P. Williams Somayya Manzoor Thomas I. Grothier Alice Piapi Valeria Fiaccadori Patrycja Wawrzyniecka Harriet A. Roddy Giulia Agliardi Claire Roddie Shimobi Onuoha Simon Thomas Shaun Cordoba Martin Pule
author_sort	Alastair Hotblack
title	Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction
title_short	Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction
title_full	Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction
title_fullStr	Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction
title_full_unstemmed	Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction
title_sort	tunable control of car t cell activity through tetracycline mediated disruption of protein–protein interaction
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dee4a8da64cb4a34bd085ebded529484
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Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction

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