Single-Cell RNA Analysis Reveals Cell-Intrinsic Functions of CAR T Cells Correlating with Response in a Phase II Study of Lymphoma Patients.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
13 Oct 2023
13 Oct 2023
Historique:
received:
20
01
2023
revised:
22
06
2023
accepted:
02
08
2023
pubmed:
4
8
2023
medline:
4
8
2023
entrez:
4
8
2023
Statut:
ppublish
Résumé
Although CD19 chimeric antigen receptor T cells (CAR-T) therapy has shown remarkable success in B-cell malignancies, a substantial fraction of patients do not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T infusion products. In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry. Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product. We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.
Identifiants
pubmed: 37540566
pii: 728314
doi: 10.1158/1078-0432.CCR-23-0178
pmc: PMC10570681
doi:
Banques de données
ClinicalTrials.gov
['NCT03068416']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4139-4152Subventions
Organisme : Vetenskapsrådet (VR)
ID : 2019-01326
Organisme : Vetenskapsrådet (VR)
ID : 2019-01721
Organisme : Cancerfonden (Swedish Cancer Society)
ID : 19 0184Pj
Organisme : Cancerfonden (Swedish Cancer Society)
ID : 20 0756 PjF
Organisme : Cancerfonden (Swedish Cancer Society)
ID : 20 1303 PjF
Organisme : AFA Försäkring (AFA Insurance)
Organisme : Lions Cancer Fund at Uppsala University Hospital
Organisme : Swedish State Support for Clinical Research
Organisme : Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
ID : KAW 2017.0003
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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