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Adoptive T-cell therapy with hexon-specific THELPER-1 cells as a treatment for refractory adenovirus infection after HSCT

Judith Feucht, Kathrin Opherk, Peter Lang, Simone Kayser, Lena Hartl, Wolfgang Bethge, Susanne Matthes-Martin, Peter Bader, Michael H. Albert, Britta Maecker-Kolhoff, Johann Greil, Hermann Einsele, Paul-Gerhardt Schlegel, Friedhelm R. Schuster, Bernhard Kremens, Claudia Rossig, Bernd Gruhn, Rupert Handgretinger and Tobias Feuchtinger

Key points

  • Adoptive transfer of THELPER-1 cells is a safe and effective treatment for refractory adenovirus infection post stem cell transplantation.

  • AdV-related mortality was 9.5% in patients with a response to adoptive T-cell transfer (overall survival 71%), compared to 100% AdV-related mortality in non-responders.

Abstract

Hematopoietic stem cell transplantation (HSCT) has improved over the last decades. However, viral infections often remain refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is the predominant disease-causing pathogen in pediatric HSCT. In a clinical trial we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of THELPER-1 phenotype, in thirty patients with AdV disease/viremia. ACT was feasible without acute toxicities or significant onset of graft-versus-host disease. ACT led to antiviral immunity in vivo up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After a follow up of 6 months post ACT, overall survival was markedly increased in responders (mean: 122 days, 15 survivors) as compared to non-responders who all died shortly after ACT (mean: 24 days, no survivors). AdV-related mortality was 100% in non-responders compared to 9.5% in responders (≥1 log reduction of DNA copies/ml post ACT). In conclusion, ex vivo ACT of AdV-specific THELPER-1 cells was well tolerated and led to successful and sustained restoration of T-cell immunity, correlated with virological response and protection from virus-related mortality. This cellular immunotherapy is a short-term available and broadly applicable treatment. The study is registered to https://www.clinicaltrialsregister.eu/ as 2005-001092-35.

  • Submitted June 9, 2014.
  • Accepted December 18, 2014.