Background: Human adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of adenovirus-specific CD4(+) T cells has been reported to be associated with sustained protection from adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4(+) T cells and no CD8(+) T cells specific for adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of adenovirus-specific CD4(+) and CD8(+) T cells in protection from adenovirus disease remains to be elucidated.
Design and methods: The presence of human adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of adenovirus-specific T-cell lines for adoptive immunotherapy.
Results: Clearance of human adenovirus viremia coincided with emergence of a coordinated CD8(+) and CD4(+) T-cell response against adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of adenovirus hexon-specific CD8(+) and CD4(+) T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human adenovirus-infected target cells.
Conclusions: This study provides a rationale and strategy for the adoptive transfer of donor-derived human adenovirus hexon-specific CD8(+) and CD4(+) T cells for the treatment of disseminated adenovirus infection after allogeneic stem cell transplantation.