title: 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 (MHC) class I-binding epitope downstream of a foreign sequence of tetanus toxin. Three p.DOM-peptide vaccines, each encoding a different WT1-derived, HLA-A2-restricted epitope, induced cytotoxic T lymphocytes (CTLs) in humanized transgenic mice expressing chimeric HLA-A2, without affecting hematopoietic stem cells. Mouse CTLs killed human leukemia cells in vitro, indicating peptide processing/presentation. Low numbers of T cells specific for these epitopes have been described in cancer patients. Expanded human T cells specific for each epitope were lytic in vitro. Focusing on human WT1(37-45)-specific cells, the most avid of the murine responses, we demonstrated lysis of primary leukemias, underscoring their clinical relevance. Finally, we showed that these human CTL kill target cells transfected with the relevant p.DOM-peptide DNA vaccine, confirming that WT1-derived epitopes are presented to T cells similarly by tumors and following DNA vaccination. Together, these data link mouse and human studies to suggest that rationally designed DNA vaccines encoding WT1-derived epitopes, particularly WT1(37-45), have the potential to induce/expand functional tumor-specific cytotoxic responses in cancer patients.
authors.affiliation: Inserm U-841, Institut Mondor de Recherche Biomédicale (IMRB), Département d'Immunologie, Dermatologie et Oncologie, Créteil, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Chaise
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Buchan
authors.forename: Jason
authors.initials: J
authors.lastname: Rice
authors.forename: Jeanine
authors.initials: J
authors.lastname: Marquet
authors.forename: Hélène
authors.initials: H
authors.lastname: Rouard
authors.forename: Mathieu
authors.initials: M
authors.lastname: Kuentz
authors.forename: Gisella E
authors.initials: GE
authors.lastname: Vittes
authors.forename: Valérie
authors.initials: V
authors.lastname: Molinier-Frenkel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Farcet
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Delfau-Larue
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D003602:Cytotoxicity, Immunologic; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006262:Health; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D014019:Tissue Donors; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D019444:Vaccines, DNA; D025721:WT1 Proteins