학술논문
Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy
Document Type
Original Paper
Author
Sheih, Alyssa; Voillet, Valentin; Hanafi, Laïla-Aïcha; DeBerg, Hannah A.; Yajima, Masanao; Hawkins, Reed; Gersuk, Vivian; Riddell, Stanley R.; Maloney, David G.; Wohlfahrt, Martin E.; Pande, Dnyanada; Enstrom, Mark R.; Kiem, Hans-Peter; Adair, Jennifer E.; Gottardo, Raphaël; Linsley, Peter S.; Turtle, Cameron J.
Source
Nature Communications. 11(1)
Subject
Language
English
ISSN
2041-1723
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.
Understanding factors that impact CAR T cell expansion in the clinic is crucial to improving its therapeutic success. Here the authors document heterogeneity in the clonal dynamics of CAR-T cells by tracking individual clones using the endogenous TCR and integration sites and provide further insights into the role of transcriptional states in clonal kinetics.
Understanding factors that impact CAR T cell expansion in the clinic is crucial to improving its therapeutic success. Here the authors document heterogeneity in the clonal dynamics of CAR-T cells by tracking individual clones using the endogenous TCR and integration sites and provide further insights into the role of transcriptional states in clonal kinetics.