title: Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer.
abstract: OBJECTIVE
  The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.
  
  
  METHODS
  Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.
  
  
  RESULTS
  Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.
  
  
  CONCLUSIONS
  Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, WA 98195-8050, USa. ndisis@u.washington.edu
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Danelle R
authors.initials: DR
authors.lastname: Wallace
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Yushe
authors.initials: Y
authors.lastname: Dang
authors.forename: Meredith
authors.initials: M
authors.lastname: Slota
authors.forename: Hailing
authors.initials: H
authors.lastname: Lu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Coveler
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Childs
authors.forename: Doreen M
authors.initials: DM
authors.lastname: Higgins
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Fintak
authors.forename: Corazon
authors.initials: C
authors.lastname: dela Rosa
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tietje
authors.forename: John
authors.initials: J
authors.lastname: Link
authors.forename: James
authors.initials: J
authors.lastname: Waisman
authors.forename: Lupe G
authors.initials: LG
authors.lastname: Salazar
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D003131:Combined Modality Therapy; D005221:Fatigue / Q000209:etiology; D005260:Female; D006261:Headache / Q000209:etiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010146:Pain / Q000209:etiology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000097:blood; D000068878:Trastuzumab; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D016212:Transforming Growth Factor beta; D000068878:Trastuzumab