title: Wilms' Tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses.
abstract: Wilms' Tumour 1 (WT1) is a zinc finger transcription factor that is over-expressed in acute myeloid leukaemia (AML). Its restricted expression in normal tissues makes it a promising target for novel immunotherapies aiming to accentuate the cytotoxic T lymphocyte (CTL) response against AML. Here we report a phase I/II clinical trial of subcutaneous peptide vaccination with two separate HLA-A2-binding peptide epitopes derived from WT1, together with a pan-DR binding peptide epitope (PADRE), in Montanide adjuvant. Eight HLA-A2-positive patients with poor risk AML received five vaccination cycles at 3-weekly intervals. The three cohorts received 0·3, 0·6 and 1 mg of each peptide, respectively. In six patients, WT1-specific CTL responses were detected using enzyme-linked immunosorbent spot assays and pWT126/HLA-A*0201 tetramer staining, after ex vivo stimulation with the relevant WT1 peptides. However, re-stimulation of these WT1-specific T cells failed to elicit secondary expansion in all four patients tested, suggesting that the WT1-specific CD8(+) T cells generated following vaccination may be functionally impaired. No correlation was observed between peptide dose, cellular immune response, reduction in WT1 mRNA expression and clinical response. Larger studies are indicated to confirm these findings.
authors.affiliation: UCL Division of Infection and Immunity, Department of Immunology, University College London, London, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Uttenthal
authors.forename: Irma
authors.initials: I
authors.lastname: Martinez-Davila
authors.forename: Adam
authors.initials: A
authors.lastname: Ivey
authors.forename: Charles
authors.initials: C
authors.lastname: Craddock
authors.forename: Frederick
authors.initials: F
authors.lastname: Chen
authors.forename: Andras
authors.initials: A
authors.lastname: Virchis
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kottaridis
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
authors.forename: Hans
authors.initials: H
authors.lastname: Stauss
authors.forename: Emma C
authors.initials: EC
authors.lastname: Morris
mesh_terms: D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D025721:WT1 Proteins; C583751:WT1 protein, human
keywords: acute myeloid leukaemia; immunotherapy; trials; tumour antigens