Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
22
12
2022
accepted:
23
05
2023
medline:
21
7
2023
pubmed:
6
7
2023
entrez:
5
7
2023
Statut:
ppublish
Résumé
In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.
Identifiants
pubmed: 37407840
doi: 10.1038/s41591-023-02415-3
pii: 10.1038/s41591-023-02415-3
pmc: PMC10353931
doi:
Substances chimiques
Antigens, CD19
0
Receptors, Antigen, T-Cell
0
CD19 molecule, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1700-1709Subventions
Organisme : Wellcome Trust
ID : 223135/Z/21/Z
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108413/A/15/D
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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