title: HER2-specific T-cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan.
abstract: OBJECTIVE
  We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4(+) T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers.
  
  
  METHODS
  Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 microg of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4(+) T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein.
  
  
  RESULTS
  CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8(+) and/or CD4(+) T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8(+) T-cell responses, two patients reacted to previously identified HER2(63-71) peptide and the other two reacted only to 146HER2 mRNA-transduced cells.
  
  
  CONCLUSIONS
  CHP-HER2 vaccine was safe and induced HER2-specific CD8(+) and/or CD4(+) T-cell immune responses.
authors.affiliation: Department of Medical Oncology and Immunology, Mie University Graduate School of Medicine, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kageyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nagata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyahara
authors.forename: Atsunori
authors.initials: A
authors.lastname: Hiasa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Naota
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imai
authors.forename: Taizo
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Masuya
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Junzo
authors.initials: J
authors.lastname: Sunamoto
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Roger
authors.initials: R
authors.lastname: Murphy
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hoffman
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry* / Q000627:therapeutic use*; D005260:Female; D005936:Glucans / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D008297:Male; D008875:Middle Aged; D000080385:Nanogels; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011094:Polyethyleneimine / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D005936:Glucans; D000080385:Nanogels; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C413692:polyethylene glycol polyethyleneimine nanogel; C009109:pullulan