title: Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.
abstract: OBJECTIVE
  The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein.
  
  
  METHODS
  Sixty-four patients with HER-2/neu-overexpressing breast, ovarian, or non-small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled.
  
  
  RESULTS
  Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein-specific T-cell immunity (P =.03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients.
  
  
  CONCLUSIONS
  The majority of patients with HER-2/neu-overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.
authors.affiliation: Division of Oncology and Department of Dermatology, University of Washington, Seattle 98195-6527, USA. ndisis@u.washington.edu
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Kristine
authors.initials: K
authors.lastname: Rinn
authors.forename: Donna
authors.initials: D
authors.lastname: Davis
authors.forename: Michael
authors.initials: M
authors.lastname: Piepkorn
authors.forename: Martin A
authors.initials: MA
authors.lastname: Cheever
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.forename: Kathy
authors.initials: K
authors.lastname: Schiffman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D016014:Linear Models; D016015:Logistic Models; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D015999:Multivariate Analysis; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D018719:Erb-b2 Receptor Tyrosine Kinases