title: Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.
abstract: Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.
authors.affiliation: Department of Surgery, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. brian.czerniecki@uphs.upenn.edu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
authors.forename: Gary K
authors.initials: GK
authors.lastname: Koski
authors.forename: Ursula
authors.initials: U
authors.lastname: Koldovsky
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Harvey
authors.initials: H
authors.lastname: Nisenbaum
authors.forename: Terry
authors.initials: T
authors.lastname: Pasha
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Fox
authors.forename: Susan
authors.initials: S
authors.lastname: Weinstein
authors.forename: Susan G
authors.initials: SG
authors.lastname: Orel
authors.forename: Robert
authors.initials: R
authors.lastname: Vonderheide
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.forename: Louis
authors.initials: L
authors.lastname: Araujo
authors.forename: Francis R
authors.initials: FR
authors.lastname: Spitz
authors.forename: Mark
authors.initials: M
authors.lastname: Rosen
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Carl
authors.initials: C
authors.lastname: June
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D007937:Leukapheresis; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D018719:Erb-b2 Receptor Tyrosine Kinases