Targeting HER-2/ neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 4; pp. 1842 - 1852
• Main Authors: Czerniecki, Brian J., Koski, Gary K., Koldovsky, Ursula, Xu, Shuwen, Cohen, Peter A., Mick, Rosemarie, Nisenbaum, Harvey, Pasha, Terry, Xu, Min, Fox, Kevin R., Weinstein, Susan, Orel, Susan G., Vonderheide, Robert, Coukos, George, DeMichele, Angela, Araujo, Louis, Spitz, Francis R., Rosen, Mark, Levine, Bruce L., June, Carl, Zhang, Paul J.
• Format: Journal Article
• Language: English
• Published: United States 15.02.2007
• Subjects: 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-4038

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/neupos 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-γ 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 CD8pos 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-γ–secreting CD4pos (85%) and CD8pos (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. [Cancer Res 2007;67(4):1842–52]