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  • Clonal kinetics and single-...
    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

    Nature communications, 01/2020, Letnik: 11, Številka: 1
    Journal Article

    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.