Induction of antigen-specific immune responses against malignant brain tumors by intramuscular injection of sindbis DNA encoding gp100 and IL-18.
We constructed pSin-SV40-HDV-SV40pA, an improved Sindbis DNA expression vector, and evaluated the potential of this vector system for brain tumor therapy. We investigated whether immunizing mice with xenogeneic DNA encoding human gp100 and mouse IL-18 would enhance the antitumor responses. To study the immune mechanisms involved in tumor regression, we examined tumor growth in B16-gp100-implanted brain tumor models using T-cell subset-depleted and IFN-gamma-neutralized mice. Hugp100/mIL-18 vaccination was also investigated for its antitumor effects against the wild-type murine B16 tumor, which expresses the murine gp100 molecule. Genetic immunization using plasmid pSin 9001 DNA codelivery of human gp100 and mouse IL-18 resulted in enhanced protective and therapeutic effects on the malignant brain tumors. The antitumor and protective effects were mediated by both CD4(+)/CD8(+) T cells and IFN-gamma. Vaccination with hugp100/mIL-18 conferred a significant survival merit to wild-type B16 tumor-harboring mice. Immunogene therapy with the improved Sindbis virus vector expressing xenogeneic gp100 and syngeneic IL-18 may be an excellent approach for developing a new treatment protocol. Thus, the Sindbis DNA system may represent a novel approach for the treatment of malignant brain tumors.
Yamanaka
Ryuya
R
Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata 951-8585, Japan. ryaman@bri.niigata-u.ac.jp
Xanthopoulos
Kleanthis G
KG
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003601:Cytotoxicity Tests, Immunologic; D004273:DNA, Neoplasm / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005910:Glioma / Q000276:immunology / Q000628:therapy / Q000821:virology; D006801:Humans; D007167:Immunotherapy; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000276:immunology / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D012845:Sindbis Virus / Q000235:genetics; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000627:therapeutic use; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004273:DNA, Neoplasm; D004279:DNA, Viral; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma