Potent vaccine therapy with dendritic cells genetically modified by the gene-silencing-resistant retroviral vector GCDNsap.
Dendritic cells (DCs) genetically modified to express tumor-associated antigens (TAAs) would be promising tools in cancer immunotherapy. However, the use of retroviral vectors for such modifications is still a challenge because of low transduction efficiency and gene silencing in DCs. We have established an efficient method to prepare such DCs by in vitro differentiation of hematopoietic progenitor cells transduced with chicken ovalbumin (OVA) cDNA via the gene-silencing-resistant retroviral vector GCDNsap packaged in vesicular stomatitis virus G protein. When c-KIT(+)/lineage(-) cells were transduced with OVA followed by expansion and differentiation, more than 90% of mature DCs expressed the transgene. Mice inoculated with those cells completely rejected the OVA-expressing tumor E.G7-OVA, and the anti-tumor effects were stronger than those observed in mice inoculated with the same number of OVA peptide-pulsed DCs. The mice harbored more cytotoxic T lymphocytes (CTLs) against E.G7-OVA and produced antibody against OVA, suggesting the generation of multiple CTLs recognizing different OVA epitopes and OVA-specific CD4(+) T cells. Successive inoculations of the transduced DCs in a therapeutic setting eradicated preexisting E.G7-OVA and prevented the progression of retransplanted tumors. Thus, this vaccine therapy may represent a potent immunotherapeutic approach for various malignant tumors that express suitable TAAs.
Nabekura
Tsukasa
T
Division of Clinical and Experimental Hematology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Otsu
Makoto
M
Nagasawa
Toshiro
T
Nakauchi
Hiromitsu
H
Onodera
Masafumi
M
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing / Q000276:immunology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics / Q000276:immunology*; D014161:Transduction, Genetic; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D010047:Ovalbumin