Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes

Abstract

The naive phenotype of cord blood (CB) T cells may reduce graft-versus-host disease after umbilical cord blood transplantation, but this naivety and their low absolute numbers also delays immune reconstitution, producing higher infection-related mortality that is predominantly related to CMV, adenovirus (Adv), and EBV. Adoptive immunotherapy with peripheral blood-derived virus-specific cytotoxic T lymphocytes (CTLs) can effectively prevent viral disease after conventional stem cell transplantation, and we now describe the generation of single cultures of CTLs from CB that are specific for multiple viruses. Using EBV-infected B cells transduced with a clinical-grade Ad5f35CMVpp65 adenoviral vector as sources of EBV, Adv, and CMV antigens, we expanded virus-specific T cells even from CB T cells with a naive phenotype. After expansion, each CTL culture contained both CD8 ؉ and CD4 ؉ T-cell subsets, predominantly of effector memory phenotype. Each CTL culture also had HLA-restricted virus-specific cytotoxic effector function against EBV, CMV, and Adv targets. The CB CTLs recognized multiple viral epitopes, including CD4-restricted Adv-hexon epitopes and immunosubdominant CD4-and CD8-restricted CMVpp65 epitopes. Notwithstanding their naive phenotype, it is therefore possible to generate trivirus-specific CTLs in a single culture of CB, which may be of value to prevent or treat viral disease in CB transplant recipients. This study is registered at www.clinicaltrials.gov as NCT00078533. (Blood.

Adoptively transferred effector cells derived from naïve rather than central memory CD8 + T cells mediate superior antitumor immunity

“…Naïve viral antigen-specific T cells in cord blood can be expanded for adoptive transfer (39). Furthermore, in preliminary studies of melanoma patients, naïve cells (CD62L ϩ CD45RO Ϫ ) represent 20 to 60% of the CD8 ϩ T cells in leukapheresis samples and can be readily transduced with TCRencoding vectors and expanded.…”

Reconstitution of Protective Immune Responses against Cytomegalovirus and Varicella Zoster Virus Does Not Require Disease Development in Pediatric Recipients of Umbilical Cord Blood Transplantation

“…Interestingly, the magnitude of the reconstitution of CMVspecific IFN-g responses in these four CMV-seronegative subjects was roughly inversely proportional to their age at the time of transplant. Although this number of subjects is too small to draw solid conclusions, it is tempting to speculate that the magnitude of this spontaneous reconstitution of CMV-specific T cell responses was somehow correlated with the extent of residual thymopoiesis in these children, consistent with the existence, generation, and selection of a public CMV-specific T cell repertoire (68,69).…”

Concise Review: Expanding Roles for Hematopoietic Cellular Therapy and the Blood Transfusion Services

“…Fascinating recent work has shown this to be possible, with the expansion of naïve T-cell subsets derived from cord units, with cytolytic activity against EBV, CMV, and adenoviruses [34]. EBV-infected B cells, transduced with a vector which enables them to express EBV, CMV, and adenovirus antigens, were used to expand virus-specific T-cells.…”