Wilms' Tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses

TY - JOUR

T1 - Wilms' Tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses

AU - Uttenthal, Benjamin

AU - Martinez-Davila, Irma

AU - Ivey, Adam

AU - Craddock, Charles

AU - Chen, Frederick

AU - Virchis, Andras

AU - Kottaridis, Panagiotis

AU - Grimwade, David

AU - Khwaja, Asim

AU - Stauss, Hans

AU - Morris, Emma C.

PY - 2014/2

Y1 - 2014/2

N2 - 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 03, 06 and 1mg 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.

AB - 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 03, 06 and 1mg 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.

KW - acute myeloid leukaemia

KW - immunotherapy

KW - tumour antigens

KW - trials

KW - CYTOTOXIC T-LYMPHOCYTES

KW - CHRONIC MYELOGENOUS LEUKEMIA

KW - BONE-MARROW TRANSPLANTATION

KW - ANTIGEN-SPECIFIC CTL

KW - GENE WT1

KW - CELL RESPONSES

KW - HIGH-AVIDITY

KW - RESIDUAL DISEASE

KW - BREAST-CANCER

KW - EXPRESSION

U2 - 10.1111/bjh.12637

DO - 10.1111/bjh.12637

M3 - Article

SN - 0007-1048

VL - 164

SP - 366

EP - 375

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 3

ER -