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

Patrick J. Hanley, Conrad Russell Young Cruz, Barbara Savoldo, Ann M. Leen, Maja Stanojevic, Mariam Khalil, William Decker, Jeffrey J. Molldrem, Hao Liu, Adrian P. Gee, Cliona M. Rooney, Helen E. Heslop, Gianpietro Dotti, Malcolm K. Brenner, Elizabeth J. Shpall, Catherine M. Bollard

Research output: Contribution to journalArticle

176 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1958-1967
Number of pages10
JournalBlood
Volume114
Issue number9
DOIs
StatePublished - Nov 19 2009
Externally publishedYes

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T-cells
Human Herpesvirus 4
Fetal Blood
Viruses
Adenoviridae
Cytotoxic T-Lymphocytes
Epitopes
Blood
T-Lymphocytes
Population
Cell culture
Phenotype
Virus Diseases
Blood Cells
Adoptive Immunotherapy
T-Lymphocyte Subsets
Stem Cell Transplantation
Graft vs Host Disease
Transplantation (surgical)
Transplants

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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. / Hanley, Patrick J.; Cruz, Conrad Russell Young; Savoldo, Barbara; Leen, Ann M.; Stanojevic, Maja; Khalil, Mariam; Decker, William; Molldrem, Jeffrey J.; Liu, Hao; Gee, Adrian P.; Rooney, Cliona M.; Heslop, Helen E.; Dotti, Gianpietro; Brenner, Malcolm K.; Shpall, Elizabeth J.; Bollard, Catherine M.

In: Blood, Vol. 114, No. 9, 19.11.2009, p. 1958-1967.

Research output: Contribution to journalArticle

Hanley, PJ, Cruz, CRY, Savoldo, B, Leen, AM, Stanojevic, M, Khalil, M, Decker, W, Molldrem, JJ, Liu, H, Gee, AP, Rooney, CM, Heslop, HE, Dotti, G, Brenner, MK, Shpall, EJ & Bollard, CM 2009, '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', Blood, vol. 114, no. 9, pp. 1958-1967. https://doi.org/10.1182/blood-2009-03-213256
Hanley, Patrick J. ; Cruz, Conrad Russell Young ; Savoldo, Barbara ; Leen, Ann M. ; Stanojevic, Maja ; Khalil, Mariam ; Decker, William ; Molldrem, Jeffrey J. ; Liu, Hao ; Gee, Adrian P. ; Rooney, Cliona M. ; Heslop, Helen E. ; Dotti, Gianpietro ; Brenner, Malcolm K. ; Shpall, Elizabeth J. ; Bollard, Catherine M. / 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. In: Blood. 2009 ; Vol. 114, No. 9. pp. 1958-1967.
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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.",
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AU - Savoldo, Barbara

AU - Leen, Ann M.

AU - Stanojevic, Maja

AU - Khalil, Mariam

AU - Decker, William

AU - Molldrem, Jeffrey J.

AU - Liu, Hao

AU - Gee, Adrian P.

AU - Rooney, Cliona M.

AU - Heslop, Helen E.

AU - Dotti, Gianpietro

AU - Brenner, Malcolm K.

AU - Shpall, Elizabeth J.

AU - Bollard, Catherine M.

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