Screening for CD19-specific chimaeric antigen receptors with enhanced signalling via a barcoded library of intracellular domains.
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
10
07
2021
accepted:
03
05
2022
pubmed:
18
6
2022
medline:
20
7
2022
entrez:
17
6
2022
Statut:
ppublish
Résumé
The immunostimulatory intracellular domains (ICDs) of chimaeric antigen receptors (CARs) are essential for converting antigen recognition into antitumoural function. Although there are many possible combinations of ICDs, almost all current CARs rely on combinations of CD3𝛇, CD28 and 4-1BB. Here we show that a barcoded library of 700,000 unique CD19-specific CARs with diverse ICDs cloned into lentiviral vectors and transduced into Jurkat T cells can be screened at high throughput via cell sorting and next-generation sequencing to optimize CAR signalling for antitumoural functions. By using this screening approach, we identified CARs with new ICD combinations that, compared with clinically available CARs, endowed human primary T cells with comparable tumour control in mice and with improved proliferation, persistence, exhaustion and cytotoxicity after tumour rechallenge in vitro. The screening strategy can be adapted to other disease models, cell types and selection conditions, and could be used to improve adoptive cell therapies and to expand their utility to new disease indications.
Identifiants
pubmed: 35710755
doi: 10.1038/s41551-022-00896-0
pii: 10.1038/s41551-022-00896-0
pmc: PMC9389442
mid: NIHMS1823414
doi:
Substances chimiques
CD19-specific chimeric antigen receptor
0
CD28 Antigens
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
855-866Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM144273
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247632
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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