title: Vaccination with human anti-trastuzumab anti-idiotype scFv reverses HER2 immunological tolerance and induces tumor immunity in MMTV.f.huHER2(Fo5) mice.
abstract: BACKGROUND
  Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity.
  
  
  METHODS
  BALB/c mice were immunized with anti-trastuzumab anti-idiotype (anti-Id) scFv (scFv40 and scFv69), which mimic human HER2. Their sera were assessed for the presence of HER2-specific Ab1' antibodies and for their ability to reduce viability of SK-OV-3 cells, a HER2-positive cancer cell line, in nude mice. MMTV.f.huHER2(Fo5) transgenic mice were immunized with scFv40 and scFv69 and, then, growth inhibition of spontaneous HER2-positive mammary tumors, humoral response, antibody isotype as well as splenocyte secretion of IL2 and IFN-γ were evaluated.
  
  
  RESULTS
  Adoptively-transferred sera from BALB/c mice immunized with scFv40 and scFv69 contain anti-HER2 Ab1' antibodies that can efficiently inhibit growth of SK-OV-3 cell tumors in nude mice. Similarly, prophylactic vaccination with anti-Id scFv69 fully protects virgin or primiparous FVB-MMTV.f.huHER2(Fo5) females from developing spontaneous mammary tumors. Moreover, such vaccination elicits an anti-HER2 Ab1' immune response together with a scFv69-specific Th1 response with IL2 and IFN-γ cytokine secretion.
  
  
  CONCLUSIONS
  Anti-trastuzumab anti-Id scFv69, used as a therapeutic or prophylactic vaccine, protects mice from developing HER2-positive mammary tumors by inducing both anti-HER2 Ab1' antibody production and an anti-HER2 Th2-dependent immune response. These results suggest that scFv69 could be used as an anti-Id-based vaccine for adjuvant therapy of patients with HER2-positive tumors to reverse immunological tolerance to HER2.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, Université Montpellier1, CRLC Val d'Aurelle Paul Lamarque, 208 rue des Apothicaires, Montpellier, F-34298, France.
authors.forename: Maha Z
authors.initials: MZ
authors.lastname: Ladjemi
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardes
authors.forename: Stephanie
authors.initials: S
authors.lastname: Corgnac
authors.forename: Veronique
authors.initials: V
authors.lastname: Garambois
authors.forename: Sebastien
authors.initials: S
authors.lastname: Morisseau
authors.forename: Bruno
authors.initials: B
authors.lastname: Robert
authors.forename: Caroline
authors.initials: C
authors.lastname: Bascoul-Mollevi
authors.forename: Imade
authors.initials: I
authors.lastname: Ait Arsa
authors.forename: William
authors.initials: W
authors.lastname: Jacot
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pouget
authors.forename: Andre
authors.initials: A
authors.lastname: Pelegrin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Navarro-Teulon
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D016466:CHO Cells; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D006224:Cricetinae; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D056724:Immunity, Humoral; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D057127:Single-Chain Antibodies / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D000068878:Trastuzumab
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases; D057127:Single-Chain Antibodies; D000068878:Trastuzumab