Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections.
Severe and fatal viral infections remain common after hematopoietic stem cell transplantation. Adoptive transfer of cytotoxic T lymphocytes (CTLs) specific for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenoviral antigens can treat infections that are impervious to conventional therapies, but broader implementation and extension to additional viruses is limited by competition between virus-derived antigens and time-consuming and laborious manufacturing procedures. We now describe a system that rapidly generates a single preparation of polyclonal (CD4(+) and CD8(+)) CTLs that is consistently specific for 15 immunodominant and subdominant antigens derived from 7 viruses (EBV, CMV, Adenovirus (Adv), BK, human herpes virus (HHV)-6, respiratory syncytial virus (RSV), and Influenza) that commonly cause post-transplant morbidity and mortality. CTLs can be rapidly produced (10 days) by a single stimulation of donor peripheral blood mononuclear cells (PBMCs) with a peptide mixture spanning the target antigens in the presence of the potent prosurvival cytokines interleukin-4 (IL4) and IL7. This approach reduces the impact of antigenic competition with a consequent increase in the antigenic repertoire and frequency of virus-specific T cells. Our approach can be readily introduced into clinical practice and should be a cost-effective alternative to common antiviral prophylactic agents for allogeneic hematopoietic stem cell transplant (HSCT) recipients.
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Texas Children's Hospital, Houston, TX, USA.
Ulrike
U
Gerdemann
Jacqueline M
JM
Keirnan
Usha L
UL
Katari
Ryu
R
Yanagisawa
Anne S
AS
Christin
Leslie E
LE
Huye
Serena K
SK
Perna
Sravya
S
Ennamuri
Stephen
S
Gottschalk
Malcolm K
MK
Brenner
Helen E
HE
Heslop
Cliona M
CM
Rooney
Ann M
AM
Leen
D000956:Antigens, Viral / Q000276:immunology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology / Q000628:therapy*
D000956:Antigens, Viral