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

Rachel S. Cooper*, Catherine Sutherland, Linda M. Smith, Graeme Cowan, Mark Barnett, Donna Mitchell, Colin McLean, Stuart Imlach, Alan Hayes, Sharon Zahra, Champa Manchanayake, Mark A. Vickers, Gerry Graham, Neil W. A. McGowan, Marc L. Turner, John D. M. Campbell, Alasdair R. Fraser

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article number1412211
Number of pages16
JournalFrontiers in Immunology
Volume15
DOIs
Publication statusPublished - 1 Jul 2024

Keywords / Materials (for Non-textual outputs)

  • cell therapy
  • Epstein-Barr virus
  • immunotherapy
  • T cell
  • potency
  • peptide
  • lymphoblastoid cell line
  • T cell receptor

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