DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance

Abstract

The Wilms tumor antigen, WT1, is associated with several human cancers, including leukemia. We evaluated WT1 as an immunotherapeutic target using our proven DNA fusion vaccine design, p.DOM-peptide, encoding a minimal tumor-derived major histocompatibility complex ( IntroductionDespite major advances in chemotherapy and hematopoietic stem cell transplantation, many patients with leukemia will relapse because of reemergence of tumor. However, complete molecular remissions have been achieved by infusion of donor lymphocytes into patients, demonstrating that reactive T cells are able to eradicate leukemic cells in vivo. 1 Recently, various leukemia-associated antigens that are recognized by cytotoxic T lymphocytes (CTLs) in the context of major histocompatibility complex (MHC) class I have been identified. 2 One promising candidate is the Wilms tumor antigen, WT1, which is expressed by the majority of acute leukemias (both acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML)), blast crisis of chronic myeloid leukemia (CML), and many solid tumors, including those of lung, breast, and colon. [3][4][5][6] The finding that blockade of WT1 function in primary leukemic cells significantly slows cell growth in vitro 7 additionally suggests that WT1 is of critical importance to the tumor phenotype and that tumor escape by simple WT1 down-modulation is unlikely to occur. In healthy adults, despite ubiquitous expression during embryogenesis, WT1 expression is limited to renal podocytes, gonadal cells, and a low frequency of hematopoietic precursor CD34 ϩ cells, 4,[8][9][10][11] where it is expressed at significantly lower levels than those described in tumors (10-to 100-fold). 4 These features indicate that WT1 could be a useful target for therapeutic vaccination.Antibodies to WT1 12-14 and WT1-peptide specific CD8 ϩ T cells [15][16][17] have been detected in AML and CML patients, confirming that tolerance is incomplete. Furthermore, the presence of WT1-specific T cells correlates with graft-versus-leukemia (GvL) effects after allogeneic stem cell transplantation in ALL patients, 18 implying that expansion of the WT1-responsive repertoire in leukemic patients may help to mediate tumor clearance.Facilitating the study of WT1-specific immunotherapeutic approaches, several MHC class I-restricted peptides have been identified, including the HLA-A*0201-restricted WT1.126 (WT1 [126][127][128][129][130][131][132][133][134] ; RMFPNAPYL) and the HLA-A*0201 and A*24-restricted WT1.235 (WT1 [235][236][237][238][239][240][241][242][243] ; CMTWNQMNL) epitopes. 19-21 T cells with specificity for WT1.126 or WT1.235 have been isolated from the peripheral blood of HLA-A2 ϩ leukemic patients, 15,22,23 although evaluation of lytic ability has been limited to HLA-A2 ϩ WT1.126-specific cells, which were shown to lyse tumor cell lines. 22 Recently, a novel HLA-A2-binding epitope, WT1.37 (WT1 37-45 ; VLDFAPPGA), was identified. 24 High-avidity T cells with WT1.37-specificity were expanded An Inside Blood analysis of this article appear...

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

“…6,39 In these studies, the optimal configuration for the induction of CD8 þ T-cell immunity consisted of a C-terminal fusion of a minimal epitope with domain 1 of FrC (here referred to as TTFC for simplicity). 6,31,40 Here, we show for the first time that the beneficial effects of TTFC fusion do also apply to full-length gene products, thereby allowing antigen presentation via multiple HLA class I alleles. What is the mechanism by which fusion with a carrier molecule enhances DNA vaccine immunogenicity?…”

Analogue peptides for the immunotherapy of human acute myeloid leukemia

“…In pDOM-epitope DNA vaccines [55,82,83] this help is provided by the first domain of tetanus toxin which can induce CD4 + T-cell responses without subverting the tumor specificity of the vaccine.…”

“…In addition, the majority of research groups have chosen to study MHC class I binding epitopes rather than MHC class II, since the effector cells in this scenario are thought to be [55,82,83] and altered WT1 peptide ligands designed for MHC class II are also being explored [84].…”

Identification and Validation of Targets for Cancer Immunotherapy: From the Bench-to-Bedside

“…This guarantees the sole expression of the HHD molecule on the cell surface, making sure that any identified CTL epitopes are HLA-A2 restricted [98]. HHD mice allow epitopes which are presented on human HLA-A2 to be examined for their ability to induce T cell responses in a variety of studies; for example STEAP, a prostate tumour antigen has been shown to be targeted by anti-tumour T cells [99] and DNA vaccines encoding Wilms tumour antigen 1 induce cytotoxic responses in mice [100] using this model system.…”