EBV T-cell immunotherapy generated by peptide selection has enhanced effector functionality compared to LCL stimulation.

Autor:	Cooper RS; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom.; Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Sutherland C; Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom., Smith LM; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Cowan G; Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom., Barnett M; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Mitchell D; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., McLean C; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Imlach S; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Hayes A; Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Zahra S; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Manchanayake C; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Vickers MA; Blood Transfusion Centre, Scottish National Blood Transfusion Service, Aberdeen, United Kingdom.; Microbiology and Immunity, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Aberdeen, United Kingdom., Graham G; Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., McGowan NWA; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Turner ML; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom., Campbell JDM; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom.; Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Fraser AR; Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Heriot Watt Research Park, Edinburgh, United Kingdom.; Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jul 01; Vol. 15, pp. 1412211. Date of Electronic Publication: 2024 Jul 01 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1412211
Abstrakt:	Adoptive immunotherapy with Epstein-Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus. We have developed a peptide-based, virus-free, serum-free closed system to manufacture a bank of virus-specific T cells (VST) for clinical use. We compared these with standard LCL-derived VST using comprehensive characterization and potency assays to determine differences that might influence clinical benefits. Multi-parameter flow cytometry revealed that peptide-derived VST had an expanded central memory population and less exhaustion marker expression than LCL-derived VST. A quantitative HLA-matched allogeneic cytotoxicity assay demonstrated similar specific killing of EBV-infected targets, though peptide-derived EBV T cells had a significantly higher expression of antiviral cytokines and degranulation markers after antigen recall. High-throughput T cell receptor-beta (TCRβ) sequencing demonstrated oligoclonal repertoires, with more matches to known EBV-binding complementary determining region 3 (CDR3) sequences in peptide-derived EBV T cells. Peptide-derived products showed broader and enhanced specificities to EBV nuclear antigens (EBNAs) in both CD8 and CD4 compartments, which may improve the targeting of highly expressed latency antigens in PTLD. Importantly, peptide-based isolation and expansion allows rapid manufacture and significantly increased product yield over conventional LCL-based approaches. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Cooper, Sutherland, Smith, Cowan, Barnett, Mitchell, McLean, Imlach, Hayes, Zahra, Manchanayake, Vickers, Graham, McGowan, Turner, Campbell and Fraser.)
Databáze:	MEDLINE
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