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

Autor:	Sheih A; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Voillet V; Vaccine and Infectious Disease Division and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Hanafi LA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., DeBerg HA; Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA., Yajima M; Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, 02215, USA., Hawkins R; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Gersuk V; Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA., Riddell SR; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA.; Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Maloney DG; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA.; Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Wohlfahrt ME; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Pande D; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Enstrom MR; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Kiem HP; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA.; Department of Pathology, University of Washington, Seattle, Washington, USA., Adair JE; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA.; Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Gottardo R; Vaccine and Infectious Disease Division and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA.; Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA., Linsley PS; Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA., Turtle CJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA. cturtle@fredhutch.org.; Department of Medicine, University of Washington, Seattle, Washington, USA. cturtle@fredhutch.org.; Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, USA. cturtle@fredhutch.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Jan 10; Vol. 11 (1), pp. 219. Date of Electronic Publication: 2020 Jan 10.
DOI:	10.1038/s41467-019-13880-1
Abstrakt:	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.
Databáze:	MEDLINE
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