Tunable control of CAR T cell activity through tetracycline mediated disruption of protein-protein interaction.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
09 11 2021
09 11 2021
Historique:
received:
05
08
2021
accepted:
25
10
2021
entrez:
10
11
2021
pubmed:
11
11
2021
medline:
29
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34754016
doi: 10.1038/s41598-021-01418-9
pii: 10.1038/s41598-021-01418-9
pmc: PMC8578617
doi:
Substances chimiques
Receptors, Chimeric Antigen
0
Minocycline
FYY3R43WGO
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
21902Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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