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Nat Commun. 2020 Jan 10;11(1):219. doi: 10.1038/s41467-019-13880-1.

Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy.

Author information

1
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.
2
Vaccine and Infectious Disease Division and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.
3
Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA.
4
Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, 02215, USA.
5
Department of Medicine, University of Washington, Seattle, Washington, USA.
6
Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.
7
Department of Pathology, University of Washington, Seattle, Washington, USA.
8
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA. cturtle@fredhutch.org.
9
Department of Medicine, University of Washington, Seattle, Washington, USA. cturtle@fredhutch.org.
10
Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA. cturtle@fredhutch.org.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has produced remarkable anti-tumor responses in patients with B-cell malignancies. However, clonal kinetics and transcriptional programs that regulate the fate of CAR-T cells after infusion remain poorly understood. Here we perform TCRB sequencing, integration site analysis, and single-cell RNA sequencing (scRNA-seq) to profile CD8+ CAR-T cells from infusion products (IPs) and blood of patients undergoing CD19 CAR-T immunotherapy. TCRB sequencing shows that clonal diversity of CAR-T cells is highest in the IPs and declines following infusion. We observe clones that display distinct patterns of clonal kinetics, making variable contributions to the CAR-T cell pool after infusion. Although integration site does not appear to be a key driver of clonal kinetics, scRNA-seq demonstrates that clones that expand after infusion mainly originate from infused clusters with higher expression of cytotoxicity and proliferation genes. Thus, we uncover transcriptional programs associated with CAR-T cell behavior after infusion.

PMID:
31924795
PMCID:
PMC6954177
DOI:
10.1038/s41467-019-13880-1
[Indexed for MEDLINE]
Free PMC Article

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