Immunogenicity and safety of xenogeneic vascular endothelial growth factor receptor-2 DNA vaccination in mice and dogs.

Sofie Denies,Laetitia Cicchelero,Ingeborgh Polis,Niek N Sanders

doi:10.18632/oncotarget.7265

Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) is an attractive target in oncology due to its crucial role in angiogenesis. In this study a DNA vaccine coding for human VEGFR-2 was evaluated in healthy mice and dogs, administered by intradermal injection and electroporation. In mice, three doses and vaccination schedules were evaluated. Cellular immune responses were measured by intracellular IFN-gamma staining and a cytotoxicity assay and antibodies by ELISA. Safety was assessed by measuring regulatory T cells and myeloid derived suppressor cells and a wound healing assay. The vaccine was subsequently evaluated in dogs, which were vaccinated three times with 100μg. Cellular immune responses were measured by intracellular IFN-gamma staining and antibodies by a flow cytometric assay. In mice, maximal cellular responses were observed after two vaccinations with 5μg. Humoral responses continued to increase with higher dose and number of vaccinations. No abnormalities in the measured safety parameters were observed. The vaccine was also capable of eliciting a cellular and humoral immune response in dogs. No adverse effects were observed, but tolerability of the electroporation was poor. This study will facilitate the evaluation of the vaccine in tumor bearing animals, ranging from rodent models to dogs with spontaneous tumors.

Highlights

It is well-known that the immune system is capable of recognizing tumor cells and to establish a specific longterm antitumor response
There was no difference in response towards tumor cells not expressing human Vascular endothelial growth factor receptor-2 (VEGFR-2), demonstrating a specific response towards the antigen
This study demonstrates that a human VEGFR-2 DNA vaccine, administered in combination with electroporation, is capable of inducing a cellular and humoral immune response in mice and dogs

Summary

Introduction

It is well-known that the immune system is capable of recognizing tumor cells and to establish a specific longterm antitumor response. Vaccination against tumor antigens holds great promises in the treatment for cancer [1]. Due to complex interactions between tumor cells and the immune system and the problem of tolerance, the translation of the theoretical potential of tumor vaccines into an effective clinical response has been difficult [2]. VEGFR-2 is strongly overexpressed on tumoral blood vessels [3]. The potential of raising an effective immune response against these tumor antigens without causing auto-immunity can be explained by the level of overexpression in tumors, reaching the threshold for T cell recognition and breaking immune tolerance [4]. As it is difficult to raise a strong immune response against self-antigens, xenogeneic vaccination, which involves the use of an antigen of a different species, has been proven to result in more potent immune responses [5]

Methods

Results

Conclusion