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

Abstract

&lt;div&gt;Abstract&lt;p&gt;Overexpression of HER-2/&lt;i&gt;neu&lt;/i&gt; (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma &lt;i&gt;in situ&lt;/i&gt; (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/&lt;i&gt;neu&lt;/i&gt; in DCIS. Before surgical resection, HER-2/&lt;i&gt;neu&lt;/i&gt;&lt;sup&gt;pos&lt;/sup&gt; DCIS patients (&lt;i&gt;n&lt;/i&gt; = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/&lt;i&gt;neu&lt;/i&gt; HLA class I and II peptides. The vaccine dendritic cells were activated &lt;i&gt;in vitro&lt;/i&gt; 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/&lt;i&gt;neu&lt;/i&gt;–HLA-A2 tetramer-staining CD8&lt;sup&gt;pos&lt;/sup&gt; 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 CD4&lt;sup&gt;pos&lt;/sup&gt; (85%) and CD8&lt;sup&gt;pos&lt;/sup&gt; (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/&lt;i&gt;neu&lt;/i&gt; expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of “immunoediting” for HER-2/&lt;i&gt;neu&lt;/i&gt;–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]&lt;/p&gt;&lt;/div&gt;