title: Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation.
abstract: Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown.
  
  
  
  Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft-versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect.
  
  
  
  A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation.
  
  
  
  Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan; Division of Transfusion, Okayama University Hospital, Okayama, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan; Division of Transfusion, Okayama University Hospital, Okayama, Japan. Electronic address: nfujii@md.okayama-u.ac.jp.
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Imada
authors.affiliation: Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Aoe
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Meguri
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Inomata
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan; Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Nishimori
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Matsuoka
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Kondo
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
mesh_terms: D001374:Azacitidine / Q000009:adverse effects* / Q000627:therapeutic use; D017809:Fatal Outcome; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000628:therapy*; D016879:Salvage Therapy; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D025721:WT1 Proteins; C583751:WT1 protein, human; D001374:Azacitidine
keywords: Wilms tumor antigen 1; azacitidine; donor lymphocyte infusion; memory phenotype