title: Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT.
abstract: Hematopoietic stem cell transplantation (HSCT) has improved over the last few decades. However, viral infections are often refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is th predominant disease-causing pathogen in pediatric HSCT. In a clinical trial, we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of the T-helper cell 1 (Th1) phenotype, in 30 patients with AdV disease or viremia. ACT was feasible with no acute toxicities or significant onset of graft-versus-host disease. ACT led to in vivo antiviral immunity for up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After ACT and a follow-up of 6 months, overall survival was markedly increased in responders (mean, 122 days; 15 survivors) compared with nonresponders who all died shortly after ACT (mean, 24 days; no survivors). AdV-related mortality was 100% in nonresponders compared with 9.5% in responders (≥1 log reduction of DNA copies per milliliter after ACT). In summary, ex vivo ACT of AdV-specific Th1 cells was well tolerated and led to successful and sustained restoration of T-cell immunity correlated with virologic response and protection from virus-related mortality. This cellular immunotherapy is a short-term available and broadly applicable treatment. The study is registered at European Union Clinical Trials Register as 2005-001092-35.
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
authors.forename: Judith
authors.initials: J
authors.lastname: Feucht
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Opherk
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
authors.forename: Simone
authors.initials: S
authors.lastname: Kayser
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
authors.forename: Lena
authors.initials: L
authors.lastname: Hartl
authors.affiliation: Department of Hematology/Oncology, University Hospital Tübingen, Tübingen, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bethge
authors.affiliation: St. Anna Children's Hospital Wien, Wien, Austria;
authors.forename: Susanne
authors.initials: S
authors.lastname: Matthes-Martin
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Frankfurt, Frankfurt, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
authors.affiliation: Department of Pediatric Hematology/Oncology, Dr. von Haunersches Kinderspital Munich, Munich, Germany;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Department of Pediatric Hematology/Oncology, Medizinische Hochschule Hannover, Hannover, Germany;
authors.forename: Britta
authors.initials: B
authors.lastname: Maecker-Kolhoff
authors.affiliation: Department of Pediatric Oncology/Hematology, University Hospital Heidelberg, Heidelberg, Germany;
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.affiliation: Department of Hematology, University Hospital Würzburg, Würzburg, Germany;
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Würzburg, Würzburg, Germany;
authors.forename: Paul-Gerhardt
authors.initials: PG
authors.lastname: Schlegel
authors.affiliation: Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;
authors.forename: Friedhelm R
authors.initials: FR
authors.lastname: Schuster
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Essen, Essen, Germany;
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kremens
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossig
authors.affiliation: Department of Pediatrics, Jena University Hospital, Jena, Germany; and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany; German Center for Infection Research, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Feuchtinger
mesh_terms: D000257:Adenoviridae Infections / Q000150:complications* / Q000209:etiology; D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D036022:Capsid Proteins / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007223:Infant; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011336:Probability; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus