HER-2 DNA and Protein Vaccines Containing Potent Th Cell Epitopes Induce Distinct Protective and Therapeutic Antitumor Responses in HER-2 Transgenic Mice

Abstract

Overexpression of the growth factor receptor HER-2 (c-erbB-2, neu) has transforming potential and occurs in ∼20–30% of breast and ovarian cancers. HER-2 is a self Ag, but Abs and T cells specific for HER-2 have been isolated from cancer patients, suggesting HER-2 may be a good target for active immunotherapy. We constructed rat HER-2 DNA and protein vaccines containing potent Th cell epitopes derived from tetanus toxin and studied their potency in two strains of mice transgenic for the rat HER-2 molecule. Vaccination with HER-2 DNA protected nontransgenic mice from tumor challenge, but induced only moderate protection in one of the tumor models. However, vaccination with the modified HER-2 protein resulted in almost complete protection from tumor challenge in both tumor models. This protection could be mediated by Abs alone. In addition, protein vaccination efficiently eliminated pre-established tumors in both models, even when vaccination occurred 9 days after tumor implantation. These data demonstrate the potential of HER-2-based vaccines as therapeutic agents for the treatment of cancers overexpressing HER-2.

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

“…These data further suggest that some of the apparent loss of HER-2/neu staining could be a result of competition from the patients' own antibody. However, these complement-fixing antibodies may also represent a tumor rejection mechanism predicted by HER-2/neu transgenic mouse models (31)(32)(33)(34)(35)(36).…”

Anti–HER-2/neuImmune Responses Are Induced before the Development of Clinical Tumors but Declined following Tumorigenesis in HER-2/neuTransgenic Mice

“…Thus, in the transgenic mouse model, eradication of HER-2/neu tumor cells may require anti-HER-2/neu antibody in addition to T cells and macrophages. Importantly, it has been shown that FVB/n transgenic mice with an activated HER-2/neu oncogene, the same strain as our FVB/n c-neu , give rise to a significant specific antibody after vaccination and tumor challenge, whereas they fail to produce anti-HER-2/neu antibody before vaccination (33). Therefore, an inadequate amount of anti-HER-2/neu antibody in unvaccinated FVB/n c-neu mice may explain why the transgenic mice spontaneously develop tumors.…”

Potent CD4+ T-cell epitope P30 enhances HER2/neu-engineered dendritic cell-induced immunity against Tg1-1 breast cancer in transgenic FVBneuN mice by enhanced CD4+ T-cell-stimulated CTL responses

“…38 It has been demonstrated that HER2/neu-and OVA-specific DNA vaccines containing P30 epitope can break self-immune tolerance in transgenic MMTV-c-neu and rat insulin promoter-mOVA mice, respectively. 21,22 In this study, we generated HER2/neu-specific To further improve the efficacy of our DC HER2/neu-P30 vaccine, some factors such as the AdV transfection efficiency and the route of vaccination are thought to be critical. For example, an efficient infection of target cells by AdVs requires two predominant viralhost cell receptor interactions.…”

“…20 It has been recently demonstrated that HER2/neu-and ovalbumin (OVA)-specific DNA vaccines containing potent Th epitope P30, derived from tetanus toxin, induced enhanced CTL responses by breaking self-immune tolerance in transgenic mouse mammary tumor virus (MMTV)-c-neu and rat insulin promoter-mOVA mice, respectively. 21,22 DCs are the most potent antigen-presenting cells in initiating antitumor immunity by presenting tumor-associated antigens to T cells and stimulating tumor-specific CTL responses. 23 DC vaccines have been extensively applied in experimental animal models and clinical trials for evaluation of antitumor immunity.…”