Journal Article

Directly Selected Cytomegalovirus-Reactive Donor T Cells Confer Rapid and Safe Systemic Reconstitution of Virus-Specific Immunity Following Stem Cell Transplantation

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

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 52, issue 1, pages 49-57
Published in print January 2011 | ISSN: 1058-4838
Published online January 2011 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1093/cid/ciq042
Directly Selected Cytomegalovirus-Reactive Donor T Cells Confer Rapid and Safe Systemic Reconstitution of Virus-Specific Immunity Following Stem Cell Transplantation

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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 cytomegalovirus-specific 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.

Journal Article.  4224 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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