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

Abstract

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/neuexpressing 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]

Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone

“…Specifically relevant to this study, the higher risk of recurrence associated with Her-2 positivity suggests the possibility of targeted therapy for patients with Her-2-positive tumors. Czerniecki et al 34 found that when patients who had Her-2-positive DCIS tumors were vaccinated with dendritic cells carrying Her-2 peptides, an inflammatory response resulted in tumorlytic antibodies, and a significant number of patients had decreased Her-2 expression within their tumor. The National Surgical Adjuvant Breast and Bowel Project (B-43) is currently comparing trastuzumab (Her-2-targeted therapy) with radiation versus radiation alone for women with Her-2-positive DCIS treated with lumpectomy.…”

Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice

“…It has recently been reported that DCs with staged IL-12 burst secretion significantly enhanced HER-2/neu-specific CD8 þ T-cell responses in clinical trials. 25 Therefore, DCs engineered to express both breast cancer Ag and cytokines may further enhance the antitumor immunity in DC-based vaccines of breast cancer for both prevention of breast cancer development and treatment of early breast cancer. Construction of fiber-modified AdV ( RGD AdVHER-2/TNF) expressing both HER-2/neu and inflammatory cytokine TNF-a and evaluation of the potential therapeutic effect of the AdV-transfected DC vaccine in treatment of early breast cancer in the Tg model are currently underway in our laboratory.…”

“…24 and stimulate antitumor immunity against challenge of HER-2/neu-positive tumor cells in vivo 22,23 leading to phaseI/II clinical trials. 25,26 However, there are limited studies evaluating the use of HER-2/neutargeted DC-based vaccination in rat HER-2/neu-gene transgenic (Tg) mice with self HER-2/neu tolerance. 27 We have previously demonstrated that vaccination of DCs transfected with AdVHER-2/neu stimulates HER-2/neuspecific CD8 þ CTL responses and immunity against challenge of HER-2-expressing colon cancer cells MCA26/HER-2 in wild-type animal model.…”

Anti-HER2 vaccines: new prospects for breast cancer therapy

“…More recently, 13 patients with HER2 over-expressing ductal in situ carcinoma were injected with DCs loaded with a mixture containing 6 HLA-I-and HLA-II-restricted peptides (i.e., 3 HER2 ECD-derived peptides and 3 HER2 ICD-derived peptides) once a week for 4 weeks before surgery [45]. Immunized patients developed a specific immune response against the peptides and presented high levels of CD4 ?…”