title: Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy.
abstract: PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30-120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen.
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. k.rezvani@imperial.ac.uk
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.forename: Behnam
authors.initials: B
authors.lastname: Jafarpour
authors.forename: Rhoda
authors.initials: R
authors.lastname: Eniafe
authors.forename: Robert Quan
authors.initials: RQ
authors.lastname: Le
authors.forename: Laura
authors.initials: L
authors.lastname: Musse
authors.forename: Carole
authors.initials: C
authors.lastname: Boss
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: A
authors.initials: A
authors.lastname: John Barrett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use; D025721:WT1 Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D019496:Cancer Vaccines; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009842:Oligopeptides; C521843:RMFPNAPYL; D022223:Vaccines, Subunit; D025721:WT1 Proteins