Targeted immunoediting of critical pathways responsible for breast cancer development: Treatment of early breast cancer using HER-2/neu pulsed dendritic cells.

PR-03

HER-2/neu over-expression plays a critical role in breast cancer development occurring in about 50-60% of high grade ductal carcinomas in situ (DCIS) lesions in the breast. HER-2/neu expression in DCIS predicts increased risk of recurrence and can often provide an escape pathway in patients treated with anti-estrogen therapy. Developing cancer vaccines targeting HER-2/neu may therefore potentially prevent a significant number of breast cancers. Patients with HER-2/neu over-expressing DCIS were invited to participate in a neoadjuvant vaccine study using HER-2/neu pulsed dendritic cells (DC). Type I polarized DC secreting high levels of IL-12 were prepared under IND BB-11043 using interferon gamma and the toll receptor 4 agonist lipopolysacharide (LPS). The DC were pulsed with 6 MHC class II binding peptides and for HLA A2+ patients the DC were also pulsed with MHC class I binding peptides. The patients received 4 weekly intranodal vaccinations consisting of 10-20 million DC. Immune assessment, HER-2/neu expression and cellular infiltrates were conducted pre and post-vaccination. Despite the presence of tolerant T cells pre-vaccine, anti-HER-2/neu specific Th1 CD4+ T cells were detected in 11 of 12 patients' peripheral blood and in sentinel nodes of 10 patients. HER-2/neu specific CD8+ T cells developed in six of eight HLA A2+ patients. These CD8+ T cells were able to recognize HER-2/neu expressing breast cancer cells. Anti-HER-2/neu complement fixing antibodies were frequently detected post-vaccination and anti-human antibodies could be detected bound to DCIS post-vaccination as well. Lymphocytic infiltrates consisting predominately of CD4 and B cells accumulated in the breast following vaccination. Both humoral and cellular anti-HER-2/neu responses could be detected for prolonged periods following vaccinations. Six of twelve patients (50%) demonstrated dramatic reductions in HER-2/neu expression post-vaccination in residual DCIS and there were associated apparent reductions in the extent of DCIS in half of the patients as well. These results demonstrate HER-2/neu pulsed type I polarized DC lead to both cellular and humoral immune activation and demonstrating for the first time a DC vaccine with significant clinical activity. Targeted immunoediting HER-2/neu using cancer vaccines may therefore be useful not only for treatment of DCIS but may also play a role in the prevention of breast cancer development.