Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation

Peggs, Karl S.; Lowdell, Mark W.; Thomson, Kirsty; Samuel, Edward; Dyer, Gemma; Armoogum, Julie; Chakraverty, Ronjon; Pang, Kwok; Mackinnon, Stephen

Abstract

Background: Adoptive transfer of virus-specific T cells may accelerate reconstitution of antigen-specific immunity and limit the morbidity and mortality of viral infections following allogeneic hematopoietic stem cell transplantation. The logistics of producing virus-specific T cells has, however, limited the application of cellular therapies, particularly following the introduction of more-recent regulatory stipulations. Methods: We investigated the ability of cytomegalovirus-specific T cells, directly isolated from donor leucapheresates on the basis of interferon γ secretion, to restore antiviral immunity in a group of 25 patients following related-donor transplantation in a single-arm phase I-II study. Selected cells were administered early following transplantation, either after the detection of cytomegalovirus DNA by polymerase chain reaction-based surveillance or prophylactically between day 40 and day 50. Results: Cell selection was successful in all cases, yielding a product biased towards CD4+ over CD8+ T cells. The target cell dose of 1 × 104 CD3+ T cells/kg of recipient weight contained a median of 2840 cytomegalovirusspecific CD4+ cells/kg and 630 cytomegalovirus- specific CD8+ cells/kg, with a median purity of 43.9% interferon γ-secreting cells. Expansions of both CD4+ and CD8+ cytomegalovirus-specific T cells were observed in vivo within days of adoptive transfer. These cells were predominantly terminally differentiated effector-memory cells and showed the same T cell receptor variable β chain (TCRBV)-restriction as the infused cells. They offered protection from reinfection in the majority of patients. Conclusions: These data indicate that application of cytomegalovirus-specific T cells generated by direct selection using γ-capture is both feasible and effective in a clinical environment. These simple in vitro methodologies should allow more widespread application of virus-specific T cell immunotherapies. © The Author 2011.

• Journal Article Type: Article
• Publication Date: Jan 1, 2011
• Journal: Clinical Infectious Diseases
• Print ISSN: 1058-4838
• Electronic ISSN: 1537-6591
• Publisher: Oxford University Press (OUP)
• Peer Reviewed: Peer Reviewed
• Volume: 52
• Issue: 1
• Pages: 49-57
• DOI: https://doi.org/10.1093/cid/ciq042
• Keywords: cytomegalovirus-reactive, donor, T cells, reconstitution, virus-specific, immunity, stem cell transplantation
• Public URL: https://uwe-repository.worktribe.com/output/970964
• Publisher URL: http://dx.doi.org/10.1093/cid/ciq042
• Related Public URLs: http://cid.oxfordjournals.org/content/52/1/49.full.pdf+html; http://cid.oxfordjournals.org/