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

Departments of ¹ Surgery, ² Biostatistics and Epidemiology, ³ Radiology, ⁴ Pathology and Laboratory Medicine, ⁵ Medicine, and ⁶ Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania and ⁷ The Center for Surgery Research, Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: Brian J. Czerniecki, Department of Surgery, University of Pennsylvania, 4 Silverstein, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-662-4392; Fax: 215-662-7476; E-mail: brian.czerniecki{at}uphs.upenn.edu.

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- 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-–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. [Cancer Res 2007;67(4):1842–52]

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