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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2602.
Expectation for DNA leukemia vaccinesOSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE
In this issue of Blood, Chaise and colleagues report that rationally designed DNA vaccines encoding Wilms tumor gene WT1-derived epitopes and a part of tetanus toxin, which is a potent, universal inducer of helper CD4+ T cells, effectively induce WT1-specific CTLs in mice and confirm that WT1-derived epitopes can induce epitope-specific human CTLs in vitro.
The Wilms tumor gene WT1 protein is overexpressed in leukemia and various types of solid tumors and thus is a potential pantumor–associated antigen and target for GVL.1 WT1 protein is highly immunogenic and thus WT1 antibodies and WT1-specific cytotoxic T lymphocytes (CTLs) are spontaneously induced in leukemia patients, and WT1-specific CTLs take part in GVL reactions following SCT. Therefore, various modalities of cancer immunotherapy targeting WT1 protein epitopes are being developed or are already in use.2 In this issue of Blood, Chaise et al report the development of a DNA vaccine targeting WT1 and clearly demonstrate the potential of this approach to induce and expand functional tumor-specific cytotoxic responses. One remarkable aspect of this particular WT1 DNA vaccine is that it also contains a portion of the tetanus toxin, which is a potent inducer of helper CD4+ T cells.3–5 Helper CD4+ T cells are needed for expansion of CD8+ CTLs, and expansion of CD8+ CTLs is dependent on the presence of helper CD4+ T cells.6,7 Indeed, helper CD4+ T cells expanded from a nontolerized tetanus-specific repertoire were critical for effective priming of CD8+ T cells following immunization with a DNA vaccine containing tetanus toxin sequences. Furthermore, this DNA vaccine was designed to contain only the first domain of the C fragment of tetanus toxin, without the second domain of the C fragment, which contains known immunogenic MHC class I–binding peptides that can compete with tumor-antigen–derived peptides for MHC class I. Because tetanus toxin binds promiscuously with MHC class II molecules, it is a universal helper epitope without restriction to specific MHC class II proteins. Therefore, this DNA vaccine particularly well-designed to induce universal helper T cells, followed by the induction of WT1-specific CTLs. Another advance described by this study is the effective use of electroporation to deliver the DNA vaccine.8 Induction of antitumor CTLs by DNA fusion vaccines is dependent on the dose of plasmid and the volume of injection. Cellular uptake of DNA appears to be a significant limiting factor for transfection and vaccine efficacy in vivo. Low DNA vaccine dose and low injection volume resulted in poor antigen expression and reduced immunogenicity in vivo. Dose and volume are limiting factors when scaling up to humans. In vivo application of electroporation to an injection site can increase DNA uptake by muscle cells and mononuclear cells, leading to increased antigen expression and enhanced immunogenicity. Electroporation may also give rise to an undefined adjuvant effect, probably mediated by local tissue damage and the resultant release of inflammatory factors. For antibody induction, DNA vaccination is generally less effective than protein vaccination. However, priming and boosting with naked DNA by using electoporation dramatically increases antibody levels. This well-designed DNA vaccine encoding the first domain of fragment C of tetanus toxin fused to 1 of 3 minimal WT1-related, HLA-A*0201–restricted epitopes (WT1. 37, WT1. 126, or WT1. 235) was shown by Chaise and colleagues to result in induction of WT1-peptide–specific CTLs in humanized transgenic mice expressing chimeric HLA-A*0201, without affecting hematopoietic stem cells. The induced WT1-peptide–specific CTLs killed target cells in a peptide-specific manner. Furthermore, these 3 WT1-epitope peptides induced peptide-specific CTLs from human peripheral blood mononuclear cells, and the induced CTLs could kill target cells in both peptide-specific and HLA-A*0201–restrictive fashion. Taken together, these results strongly indicate that rationally-designed DNA vaccines encoding WT1-derived epitopes, particularly WT137-45, have the potential to induce and expand functional tumor-specific cytotoxic responses in cancer patients, and that these DNA vaccines should also be useful in clinical settings. We await clinical trial results with enthusiasm.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
