title: Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia.
abstract: To determine whether the leukemia-associated Wilms tumor antigen (WT1) contributes to a graft-versus-leukemia (GVL) effect after allogeneic stem-cell transplantation (SCT) for acute lymphoblastic leukemia (ALL), we studied CD8(+) T-cell responses to WT1 in 10 human lymphocyte antigen (HLA)-A*0201-positive ALL patients during the early phase of immune recovery after SCT (days 30-120). Seven of 10 patients had detectable WT1 expression in their peripheral blood (PB) before SCT by quantitative reverse-transcription polymerase chain reaction. Using WT1/HLA-A*0201 tetramers and intracellular interferon-gamma (IFN-gamma) staining, WT1(+) CD8(+) T-cell responses after SCT were found only in patients with detectable WT1 expression before SCT (5 of 7 vs. 0 of 3; P < .05). To monitor the kinetics of WT1(+) CD8(+) T-cell responses and disease regression after SCT, absolute WT1(+) CD8(+) T-cell numbers and WT1 expression were studied for each time point. The emergence of WT1(+) CD8(+) T cells was associated with a decrease in WT1 expression, suggesting a WT1-driven GVL effect. Loss of WT1(+) CD8(+) T-cell responses was associated with reappearance of WT1 transcripts, consistent with a molecular relapse (P < .001). WT1(+) CD8(+) T cells had a predominantly effector-memory phenotype (CD45RO(+) CD27(-)CD57(+)) and produced IFN-gamma. Our results support the immunogenicity of WT1 after SCT for ALL and highlight the potential for WT1 vaccines to boost GVL after SCT for ALL.
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA. rezvanik@nhlbi.nih.gov
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D000293:Adolescent; D000328:Adult; D002051:Burkitt Lymphoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes; D002648:Child; D003587:Cytomegalovirus / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000628:therapy / Q000821:virology; D005260:Female; D006086:Graft vs Host Disease; D020544:Graft vs Leukemia Effect; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025721:WT1 Proteins