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

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

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD19 / immunology*
  • Clonal Selection, Antigen-Mediated / immunology
  • Humans
  • Immunotherapy*
  • Immunotherapy, Adoptive*
  • Kinetics
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chimeric Antigen / immunology*
  • Sequence Analysis, RNA
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Transcriptome

Substances

  • Antigens, CD19
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen