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Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive |
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| Authors: | Yasmin R. Mohseni Adeel Saleem Sim L. Tung Caroline Dudreuilh Cameron Lang Qi Peng Alessia Volpe George Adigbli Amy Cross Joanna Hester Farzin Farzaneh Cristiano Scotta Robert I. Lechler Fadi Issa Gilbert O. Fruhwirth Giovanna Lombardi |
| Affiliation: | 1. MRC Centre for Transplantation Immunology, School of Immunology and Microbial Sciences, King's College London, London, UK;2. MRC Centre for Transplantation Immunology, School of Immunology and Microbial Sciences, King's College London, London, UK Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Studies, King's College London, London, UK Department of Haematology and Precision Medicine, Kings College Hospital, London, UK;3. Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Studies, King's College London, London, UK;4. Transplantation Research & Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK;5. Department of Haematological Medicine, School of Cancer and Pharmaceutical Studies, King's College London, London, UK;6. Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Studies, King's College London, London, UK These authors are co-senior authors.;7. MRC Centre for Transplantation Immunology, School of Immunology and Microbial Sciences, King's College London, London, UK These authors are co-senior 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. |
| Keywords: | Cell therapy Chimeric antigen receptor IL-10 Regulatory T cell Suppression |