期刊
CANCER DISCOVERY
卷 11, 期 9, 页码 2186-2199出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-1677
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资金
- NIH [CA232361, CA233285]
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- Stand Up To Cancer Innovative Research Grant [SU2C-AACR-IRG 12-17]
- CIHR Doctoral Foreign Study Award [433117]
- NIH/National Child Health and Human Development [T32HD043021]
- NCI [K12CA076931]
- NIH Medical Scientist Training Program [T32 GM07170]
- Blavatnik Family Fellowship in Biomedical Research
- American Association for Cancer Research
- SU2C
The study revealed that chronic IFN signaling regulated by IRF7 is associated with poor CAR T-cell persistence, while the TCF7 regulon is maintained in effector T cells among patients with long-term CAR T-cell persistence. These findings offer key insights into the molecular determinants of clinical CAR T-cell function.
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 naive 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. SIGNIFICANCE: To improve clinical outcomes for CAR T-cell therapy, there is a need to understand the molecular determinants of CAR T-cell persistence. These data represent the largest clinically annotated molecular atlas in CAR T-cell therapy to date, and significantly advance our understanding of the mechanisms underlying therapeutic efficacy.
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