Preclinical Testing Of A Novel Anti-Angiogenic Vaccine Targeting Human Vegf

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAINTRODUCTION: Targeting VEGF is a well-established way of inhibiting angiogenesis and is applied in different tumor types in combination with chemotherapy. The humanized monoclonal antibody against VEGF, bevacizumab, is able to help reverse the immunosuppressive state in cancer patients. In order to circumvent the specific drawbacks of bevacizumab treatment while making use of the hypothesized synergy of anti-angiogenic therapy and immunotherapy, a therapeutic cancer vaccine targeting VEGF was developed.METHODS: The vaccine consists of a synthetic truncated peptidi mimic of the VEGF protein (hVEGF26-104) emulsified with the adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE). Truncation of the sequence combined with minor alterations in the primary amino acid structure to prevent dimerization, maintains the three dimensional cysteine knot structure of the full length VEGF protein, transforming this peptide mimic into an immunogen.RESULTS: Active immunisation studies were conducted in mice and rats. In both species high anti-VEGF antibody titers were induced as determined by ELISA. Furthermore, in a VEGF-specific proliferation assay using Ba/F3-VEGFR2 cells it was shown that the induced antibodies were able to block the functional binding of VEGF to VEGFR2.A passive immunisation study with rat antisera was carried out in LS174 T human colon carcinoma-bearing nude mice. Treatment with antisera generated with the VEGF26-104 immunogen significantly inhibited tumor growth (93% reduction in tumor volume; pu003c0.0001) and tumor microvessel density (MVD) (54% reduction; pu003c0.0001) compared to saline treated mice. This was equally effective as treatment with bevacizumab.A final preclinical safety and immunogenicity study in cynomolgus macaques showed that besides a temporary increase in body temperature and mild to moderate injection site reactions, the immunisation proved to be safe. In 31/32 immunised macaques a strong anti-VEGF antibody response (titers up to 1:21,870) was induced. Moreover, the antisera were able to inhibit the binding of bevacizumab to VEGF in a competition ELISA, which illustrates the functional activity of the antisera generated.CONCLUSIONS: The preclinical work on hVEGF26-104/RFASE shows that it can be safely administered and is able to induce polyclonal anti-VEGF antibodies neutralizing VEGF activity and have potent tumor-inhibiting capacities. At this moment the first-in-human phase I clinical trial is running to investigate the safety and tolerability of this vaccine ([NCT02237638][1]).Citation Format: Madelon Q. Wentink, Peter Timmerman, Hans J. van der Vliet, Tanja D. de Gruijl, Henk M.W. Verheul, Arjan W. Griffioen. Preclinical testing of a novel anti-angiogenic vaccine targeting human VEGF. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2496. doi:10.1158/1538-7445.AM2015-2496 [1]: /lookup/external-ref?link_type=CLINTRIALGOVu0026access_num=NCT02237638u0026atom=%2Fcanres%2F75%2F15_Supplement%2F2496.atom