DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance.
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.
Chaise
Coralie
C
Inserm U-841, Institut Mondor de Recherche Biomédicale (IMRB), Département d'Immunologie, Dermatologie et Oncologie, Créteil, France.
Buchan
Sarah L
SL
Rice
Jason
J
Marquet
Jeanine
J
Rouard
Hélène
H
Kuentz
Mathieu
M
Vittes
Gisella E
GE
Molinier-Frenkel
Valérie
V
Farcet
Jean-Pierre
JP
Stauss
Hans J
HJ
Delfau-Larue
Marie-Hélène
MH
Stevenson
Freda K
FK
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*
D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D019444:Vaccines, DNA; D025721:WT1 Proteins