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Cancer Discovery
Cancer Discovery
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Research Article

Integrative bulk and single-cell profiling of pre-manufacture 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 and Kai Tan
Gregory M Chen
1University of Pennsylvania
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Changya Chen
2Children's Hospital of Philadelphia
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Rajat K Das
2Children's Hospital of Philadelphia
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Peng Gao
3Pediatrics, Children's Hospital of Philadelphia
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Chia-Hui Chen
2Children's Hospital of Philadelphia
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Shovik Bandyopadhyay
4Department of Biological Sciences, Purdue Univeristy
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Yang-Yang Ding
5Oncology, Children's Hospital of Philadelphia
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Yasin Uzun
2Children's Hospital of Philadelphia
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Wenbao Yu
2Children's Hospital of Philadelphia
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Qin Zhu
1University of Pennsylvania
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Regina M Myers
2Children's Hospital of Philadelphia
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Stephan A. Grupp
6Division of Oncology, Children's Hospital of Philadelphia
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David M. Barrett
7Tmunity Therapeutics, Inc.
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Kai Tan
8Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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  • For correspondence: tank1@email.chop.edu
DOI: 10.1158/2159-8290.CD-20-1677
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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. In order to interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the pre manufacture T-cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-Seq on sorted T-cell subsets from all 71 patients, followed by paired CITE-Seq and single-cell ATAC-Seq on T-cells from 6 of these patients. We found that chronic interferon 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.

  • Received November 17, 2020.
  • Revision received March 3, 2021.
  • Accepted April 1, 2021.
  • Copyright ©2021, American Association for Cancer Research.
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This OnlineFirst version was published on April 5, 2021
doi: 10.1158/2159-8290.CD-20-1677

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Integrative bulk and single-cell profiling of pre-manufacture 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 and Kai Tan
Cancer Discov April 5 2021 DOI: 10.1158/2159-8290.CD-20-1677

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Integrative bulk and single-cell profiling of pre-manufacture 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 and Kai Tan
Cancer Discov April 5 2021 DOI: 10.1158/2159-8290.CD-20-1677
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