title: Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant.
abstract: Adoptive transfer of virus-specific T cells can prevent and treat serious infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus (Adv) after allogeneic hematopoietic stem cell transplant. It has, however, proved difficult to make this approach widely available since infectious virus and viral vectors are required for T cell activation, followed by an intensive and prolonged culture period extending over several months. We now show that T cells targeting a range of viral antigens derived from EBV, CMV, and Adv can be reproducibly generated in a single culture over a 2-3-week period, using methods that exclude all viral components and employ a much-simplified culture technology. When administered to recipients of haploidentical (n = 5), matched unrelated (n = 3), mismatched unrelated (n = 1) or matched related (n = 1) transplants with active CMV (n = 3), Adv (n = 1), EBV (n = 2), EBV+Adv (n = 2) or CMV+Adv (n = 2) infections, the cells produced complete virological responses in 80%, including all patients with dual infections. In each case, a decrease in viral load correlated with an increase in the frequency of T cells directed against the infecting virus(es); both immediate and delayed toxicities were absent. This approach should increase both the feasibility and applicability of T cell therapy. The trial was registered at www.clinicaltrials.gov as NCT01070797.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gerdemann
authors.forename: Usha L
authors.initials: UL
authors.lastname: Katari
authors.forename: Anastasia
authors.initials: A
authors.lastname: Papadopoulou
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Keirnan
authors.forename: John A
authors.initials: JA
authors.lastname: Craddock
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Caridad A
authors.initials: CA
authors.lastname: Martinez
authors.forename: Alana
authors.initials: A
authors.lastname: Kennedy-Nasser
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Leung
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Gottschalk
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000257:Adenoviridae Infections / Q000628:therapy*; D000293:Adolescent; D019264:Adoptive Transfer; D000956:Antigens, Viral / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000628:therapy; D004267:DNA Viruses / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000628:therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006566:Herpesviridae Infections / Q000628:therapy*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D000956:Antigens, Viral