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Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)2522-2530
Number of pages9
JournalEuropean Journal of Immunology
Volume51
Issue number10
DOIs
Accepted/In press2021
PublishedOct 2021

Bibliographical note

Funding Information: We thank Dr. Kate Milward (University of Oxford) for the pCAG.IL-10.eGFP plasmid, Dr. Marc Martinez-Llordella for the B-LCLs, and Dr. Carlo Scala/Miss Kholood Basahel (all King's College London) for technical help with lentivirus production. The authors received funding from the Medical Research Council (MRC Centre for Transplantation at KCL: MR/J006742/1), the British Heart Foundation (TG/16/2/32657 to GL), and Cancer Research UK (C48390/A21153 to GF). CD was funded by Societe Francophone de Transplantation and the European Society of Organ Transplantation. FI is a Wellcome Trust CRCD Fellow. This work was further supported by the Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to King's Health Partners, and the Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z). This work was further supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas? NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility. Views expressed are those of the authors and not necessarily those of the NHS, NIHR, or DoH. Funding Information: We thank Dr. Kate Milward (University of Oxford) for the pCAG.IL‐10.eGFP plasmid, Dr. Marc Martinez‐Llordella for the B‐LCLs, and Dr. Carlo Scala/Miss Kholood Basahel (all King's College London) for technical help with lentivirus production. The authors received funding from the Medical Research Council (MRC Centre for Transplantation at KCL: MR/J006742/1), the British Heart Foundation (TG/16/2/32657 to GL), and Cancer Research UK (C48390/A21153 to GF). CD was funded by Societe Francophone de Transplantation and the European Society of Organ Transplantation. FI is a Wellcome Trust CRCD Fellow. This work was further supported by the Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to King's Health Partners, and the Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z). This work was further supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility. Views expressed are those of the authors and not necessarily those of the NHS, NIHR, or DoH. Publisher Copyright: © 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.

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