Integrative bulk and single-cell profiling of premanufacture t-cell populations reveals factors mediating long-term persistence of car t-cell therapy

Gregory M. Chen, Changya Chen, Rajat K. Das, Peng Gao, Chia Hui Chen, Shovik Bandyopadhyay, Yang Yang Ding, Yasin Uzun, Wenbao Yu, Qin Zhu, Regina M. Myers, Stephan A. Grupp, David M. Barrett, Kai Tan

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between-and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence. These findings provide key insights into the underlying molecular determinants of clinical CAR T-cell function.

Original languageEnglish (US)
Pages (from-to)2186-2199
Number of pages14
JournalCancer Discovery
Volume11
Issue number9
DOIs
StatePublished - Sep 2021

All Science Journal Classification (ASJC) codes

  • Oncology

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