Adjuvant effect of HER-2/neu-specific adenoviral vector stimulating CD8⁺ T and natural killer cell responses on anti-HER-2/neu antibody therapy for well-established breast tumors in HER-2/neu transgenic mice.

Abstract

Approximately one third of patients with advanced human epidermal growth factor receptor 2 (HER-2)/neu-positive breast cancer respond to trastuzumab monotherapy, a humanized anti-HER-2/neu antibody. However, de novo and acquired antibody resistance is one of the major limitations of trastuzumab therapy warranting the search for other therapeutic strategies. One of the most remarkable features of adenovirus (AdV)-based vaccine is its ability to induce exceptionally high and sustained frequencies of transgene product-specific CD8+ T-cell responses. In this study, we constructed two recombinant AdVs (AdVOVA and AdVHER-2) expressing ovalbumin (OVA) and HER-2/neu, and assessed AdV-induced antigen-specific cellular immune responses and preventive/therapeutic antitumor immunity. We demonstrate that AdVOVA stimulates efficient OVA-specific CD8+ cytotoxic T lymphocyte (CTL) and natural killer responses, leading to preventive long-term immunity against OVA-expressing BL6-10ova melanoma in wild-type C56BL/6 mice. We further demonstrate that AdVHER-2 stimulates HER-2/neu-specific CD8+ CTL responses, leading to a significant reduction in breast carcinogenesis in transgenic FVBneuN mice (P<0.05), but has little therapeutic effect on pre-existing Tg1-1 tumor even at early stage (15 mm3). In contrast, the anti-HER-2/neu antibody therapy is capable of completely inhibiting Tg1-1 tumor growth at early stage, but fails to eradicate well-established Tg1-1 breast tumor (100 mm3). Interestingly, a combinatorial immunotherapy of anti-HER-2/neu antibody with AdVHER-2 vaccine was capable of curing 4 of 10 studied mice bearing well-established Tg1-1 breast tumors and significantly delaying in death of the remaining six tumor-bearing mice (P<0.05). Taken together, our results suggest an adjuvant effect of AdVHER-2 on anti-HER-2/neu antibody therapy for well-established breast tumor in transgenic FVBneuN mice, and this combinatorial immunotherapy of trastuzumab with AdVHER-2 vaccine may be used as a new therapeutic strategy for treatment of advanced HER-2/neu-positive breast cancer.