title: HER2 dendritic cell vaccines.
abstract: HER2/neu, a tumor antigen overexpressed by a third of breast cancers, is a potential target for vaccine therapies. A particularly potent immunization strategy to induce T-cell responses against tumor antigens is to use dendritic cells (DCs) loaded with the tumor antigen. We performed two small studies to test the safety, feasibility, and immunologic and clinical responses to immunizations with in vitro-generated DCs loaded with either a human leukocyte antigen A2-restricted peptide fragment of the extracellular domain of the tumor antigen HER2 (E75) or a HER2 intracellular domain (ICD) protein in patients with high-risk resected breast cancer or metastatic cancers expressing HER2. There were no toxicities due to the immunizations in any of the patients. In the study of DCs loaded with the E75 peptide, 1 of 6 patients with metastatic HER2-expressing malignancies who completed all immunizations had stable disease for 6 months; the remainder of the patients had progressive disease. Delayed-type hypersensitivity (DTH) reactivity (2-3 mm of induration) at E75-loaded DC injection sites was observed in 2 of 5 patients evaluated but was similar at the unloaded DC injection sites. In 2 patients, the DTH sites underwent biopsy and a perivascular infiltrate of CD4 and CD8 cells was demonstrated, which was greater in the E75-loaded DC injection sites than in the unloaded DC sites. In the pilot study of ICD-loaded DC in patients with high-risk resected breast cancer, all 3 patients enrolled had no evidence of recurrence at a follow-up of up to 2.5 years. Intracellular domain-specific T-cell responses were detected directly from the peripheral blood by enzyme-linked immunospot and proliferation assay in 2 patients. We conclude that it is feasible and safe to generate and administer HER2-loaded DCs to patients with advanced HER2/neu-expressing malignancies and high-risk breast cancer. The magnitude of the immune responses generated is fairly modest, and more potent DC loading and maturation strategies will be necessary to optimize these vaccines.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. morse004@mc.duke.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Kirsten
authors.initials: K
authors.lastname: Colling
authors.forename: Amy
authors.initials: A
authors.lastname: Hobeika
authors.forename: Ken
authors.initials: K
authors.lastname: Grabstein
authors.forename: Martin A
authors.initials: MA
authors.lastname: Cheever
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007114:Immunization; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D012307:Risk Factors; D013601:T-Lymphocytes; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases