Article: article from journal or magazin.
Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.
Publication types: Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Antibody-Dependent Cell Cytotoxicity, Breast Neoplasms/immunology, Breast Neoplasms/therapy, Cancer Vaccines/immunology, Cancer Vaccines/therapeutic use, Carcinoma, Intraductal, Noninfiltrating/immunology, Carcinoma, Intraductal, Noninfiltrating/therapy, Dendritic Cells/immunology, Dendritic Cells/secretion, Humans, Immunotherapy, Adoptive/methods, Interferon-gamma/immunology, Interferon-gamma/pharmacology, Interleukin-12/immunology, Interleukin-12/secretion, Leukapheresis, Lipopolysaccharides/immunology, Lipopolysaccharides/pharmacology, Monocytes/drug effects, Monocytes/immunology, Receptor, erbB-2/immunology, T-Lymphocytes/immunology
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