title: Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).
abstract: Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Oliver C
authors.initials: OC
authors.lastname: Goodyear
authors.forename: Mike
authors.initials: M
authors.lastname: Dennis
authors.forename: Nadira Y
authors.initials: NY
authors.lastname: Jilani
authors.forename: Justin
authors.initials: J
authors.lastname: Loke
authors.forename: Shamyla
authors.initials: S
authors.lastname: Siddique
authors.forename: Gordon
authors.initials: G
authors.lastname: Ryan
authors.forename: Jane
authors.initials: J
authors.lastname: Nunnick
authors.forename: Rahela
authors.initials: R
authors.lastname: Khanum
authors.forename: Manoj
authors.initials: M
authors.lastname: Raghavan
authors.forename: Mark
authors.initials: M
authors.lastname: Cook
authors.forename: John A
authors.initials: JA
authors.lastname: Snowden
authors.forename: Mike
authors.initials: M
authors.lastname: Griffiths
authors.forename: Nigel
authors.initials: N
authors.lastname: Russell
authors.forename: John
authors.initials: J
authors.lastname: Yin
authors.forename: Charles
authors.initials: C
authors.lastname: Crawley
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.forename: Ram
authors.initials: R
authors.lastname: Malladi
authors.forename: Charles F
authors.initials: CF
authors.lastname: Craddock
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology* / Q000628:therapy; D018655:Lymphocyte Count; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D000939:Epitopes; D052118:Lysosomal-Associated Membrane Protein 1; D001374:Azacitidine