title: CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.
abstract: Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity.
authors.affiliation: Blood and Marrow Transplantation Program, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Locke
authors.affiliation: Blood and Marrow Transplantation Program, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pidala
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Barry
authors.initials: B
authors.lastname: Storer
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.affiliation: Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah Medical Center, Salt Lake City, Utah.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.affiliation: Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington; Cancer Care Division, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Chauncey
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jacobsen
authors.affiliation: Department of Stem Cell Transplantation, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Irwin
authors.initials: I
authors.lastname: Walker
authors.affiliation: Hoffman LaRoche, Nutley, New Jersey.
authors.forename: Susan
authors.initials: S
authors.lastname: Light
authors.affiliation: Haemato-Oncology Unit, Royal Marsden Hospital, Sutton, United Kingdom.
authors.forename: Bronwen E
authors.initials: BE
authors.lastname: Shaw
authors.affiliation: Blood and Marrow Transplantation Program, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Francisca
authors.initials: F
authors.lastname: Beato
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, California.
authors.forename: Ginna G
authors.initials: GG
authors.lastname: Laport
authors.affiliation: Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, California.
authors.forename: Auayporn
authors.initials: A
authors.lastname: Nademanee
authors.affiliation: Blood and Marrow Transplant Centre, Department of Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.affiliation: Department of Hematology/Transplantation, Hospital Saint Louis, Paris, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Socie
authors.affiliation: Blood and Marrow Transplantation Program, Moffitt Cancer Center, Tampa, Florida. Electronic address: claudio.anasetti@moffitt.org.
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D000077561:Daclizumab; D004311:Double-Blind Method; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007223:Infant; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects*; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C508017:IL2RA protein, human; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D000077561:Daclizumab
keywords: Antitumor immunity; Daclizumab; Regulatory T cells