Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 51, Issue 10, Pages 2522-2530Publisher
WILEY
DOI: 10.1002/eji.202048934
Keywords
Cell therapy; Chimeric antigen receptor; IL-10; Regulatory T cell; Suppression
Categories
Funding
- Medical Research Council (MRC Centre for Transplantation at KCL) [MR/J006742/1]
- British Heart Foundation [TG/16/2/32657]
- Cancer Research UK [C48390/A21153]
- Societe Francophone de Transplantation
- European Society of Organ Transplantation
- Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre
- Wellcome/EPSRC Centre for Medical Engineering [WT203148/Z/16/Z]
- NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London
- NIHR Clinical Research Facility
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This study demonstrates the enhanced specificity and suppressive capacity of engineered Tregs with HLA-A2 CAR, IL-10 expression, and an imaging reporter, providing a proof-of-principle for next-generation Treg therapy in transplantation.
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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