title: Systemic administration of a novel immune-stimulatory pseudovirion suppresses lung metastatic melanoma by regionally enhancing IFN-γ production.
abstract: OBJECTIVE
  Cancer immunotherapy has encountered many difficulties in the face of the expectation to eradicate cancer, and new breakthroughs are required. We have previously shown that UV-inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) induce immunity against multiple tumor types. In this study, a novel pseudovirion that stimulates more robust antitumor immunity was designed for cancer treatment.
  
  
  METHODS
  First, we found that culturing murine splenocytes with HVJ-E in combination with interleukin (IL)-12 resulted in a remarkable increase in IFN-γ production compared with that observed in splenocytes cultured with IL-12 alone. The synergistic effects of HVJ-E and IL-12 on IFN-γ production were caused by viral F proteins independently of HVJ-E fusion activity and not by hemagglutination from hemagglutinin-neuraminidase (HN) proteins. We next constructed HN-depleted HVJ-E expressing the Fc region of immunoglobulin G (IgG) on the envelope and single-chain IL-12 containing the ZZ domain of protein A to produce an IL-12-conjugated HVJ-E particle without hemagglutinating activity.
  
  
  RESULTS
  IL-12-conjugated HVJ-E dramatically enhanced the amount of IFN-γ produced by immune cells. Intratumoral injection of IL-12-conjugated HVJ-E eradicated murine melanomas more effectively than injection of wild-type HVJ-E through increased production of melanoma-specific CTLs. IL-12-conjugated HVJ-E preferentially accumulated in the lungs after systemic administration. When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12-conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-γ in the lungs and generating large numbers of melanoma-specific CTLs.
  
  
  CONCLUSIONS
  IL-12-conjugated HVJ-E is a promising tool for the treatment of cancers, including lung metastasis.
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Saga
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D000882:Haplorhini; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D029082:Sendai virus / Q000276:immunology* / Q000528:radiation effects; D014760:Viral Fusion Proteins / Q000276:immunology; D014771:Virion / Q000276:immunology* / Q000528:radiation effects
chemical_list: D007141:Immunoglobulin Fc Fragments; D014760:Viral Fusion Proteins; D018664:Interleukin-12; D007371:Interferon-gamma