Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo

Abstract

Overexpression of HER-2 and VEGF plays a key role in the development and metastasis of several human cancers. Many FDA-approved therapies targeting both HER-2 (Trastuzumab, Herceptin) and VEGF (Bevacizumab, Avastin) are expensive, have unacceptable toxicities and are often associated with the development of resistance. Here, we evaluate the dual antitumor effects of combining designed particular HER-2 peptide vaccine with VEGF peptide mimics. In vitro, HER-2 phosphorylation and antibody-dependent cellular toxicity were used to validate whether combining HER-2- and VEGF-targeting therapies would be effective. Moreover, a two-pronged approach was tested in vivo: (1) active immunotherapy with conformational HER-2 B-cell epitope vaccines and (2) anti-angiogenic therapy with a peptide structured to mimic VEGF. A transplantable BALB/c mouse model challenged with TUBO cells was used to test the effects of the HER-2 peptide vaccine combined with VEGF peptide mimics. Tumor sections after treatment were stained for blood vessel density and actively dividing cells. Our results show that immunization with an HER-2 peptide epitope elicits high affinity HER-2 native antibodies that are effective in inhibiting tumor growth in vivo, an effect that is enhanced by VEGF peptide mimics. We demonstrate that the combination of HER-2 and VEGF peptides induces potent anti-tumor and anti-angiogenic responses.