Reconstitution of EBV-directed T cell immunity by adoptive transfer of peptide-stimulated T cells in a patient after allogeneic stem cell transplantation for AITL

PLoS Pathog. 2022 Apr 22;18(4):e1010206. doi: 10.1371/journal.ppat.1010206. eCollection 2022 Apr.

Abstract

Reconstitution of the T cell repertoire after allogeneic stem cell transplantation is a long and often incomplete process. As a result, reactivation of Epstein-Barr virus (EBV) is a frequent complication that may be treated by adoptive transfer of donor-derived EBV-specific T cells. We generated donor-derived EBV-specific T cells by stimulation with peptides representing defined epitopes covering multiple HLA restrictions. T cells were adoptively transferred to a patient who had developed persisting high titers of EBV after allogeneic stem cell transplantation for angioimmunoblastic T-cell lymphoma (AITL). T cell receptor beta (TCRβ) deep sequencing showed that the T cell repertoire of the patient early after transplantation (day 60) was strongly reduced and only very low numbers of EBV-specific T cells were detectable. Manufacturing and in vitro expansion of donor-derived EBV-specific T cells resulted in enrichment of EBV epitope-specific, HLA-restricted T cells. Monitoring of T cell clonotypes at a molecular level after adoptive transfer revealed that the dominant TCR sequences from peptide-stimulated T cells persisted long-term and established an EBV-specific TCR clonotype repertoire in the host, with many of the EBV-specific TCRs present in the donor. This reconstituted repertoire was associated with immunological control of EBV and with lack of further AITL relapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Epitopes
  • Epstein-Barr Virus Infections*
  • Hematopoietic Stem Cell Transplantation*
  • Herpesvirus 4, Human / physiology
  • Humans
  • Peptide T
  • Peptides
  • T-Lymphocytes

Substances

  • Epitopes
  • Peptides
  • Peptide T

Grants and funding

AG was supported by the ZIM fund (KF 2766401FRO, Federal Ministry for Economic Affairs and Energy Germany), the BayImmuNet Consortium of the Bayerische Staatsministerium für Bildung und Kultur, Wissenschaft und Kunst (Government of Bavaria), and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projektnummer 324392634 - TRR 221 and SFB643. MFLC was supported by scholarships from Berlin School of Integrative Oncology (BSIO), Charité – Universitätsmedizin Berlin, and the Mexican National Council of Science and Technology (CONACYT). AMo was supported by Wilhelm Sander-Stiftung (project 2018.135.1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.