Malignant glioma is characterized by early local invasion, microsatellite infiltration of healthy CNS tissue and dispersion of tumor cells in distant parenchyma. These characteristics significantly hamper the success of surgical or radiation treatment, since the tumor cannot be treated in its entirety without unacceptable damage to surrounding normal brain. Harnessing the patients'immune system to generate anti-tumor responses has the potential to overcome treatment limits imposed by the invasive properties of glioma. Immunotherapy approaches target glioma cells directly, via antigenic signatures unique to tumor, or indirectly by attacking mechanisms supporting glioma growth, invasion or immune evasion. Efficacious cancer vaccines may require combined responses directed against the tumor itself and mechanisms of immune tolerance. We generated a new immunization platform based on Coxsackievirus A21 (CAV21), a common- cold causing enterovirus. This includes (i) a new technology achieving permanent genetic stability of viral vectors for the delivery of foreign antigens;(ii) mice transgenic for the CAV21 receptor, the human intercellular adhesion molecule-1 (hICAM-1). We established a rodent model for the common cold in hICAM-1 transgenic mice, which exhibit modest virus replication in the respiratory tract and mild airway inflammation upon CAV21 infection, similar to humans. CAV21 infection causes complex inflammatory reactions that engage multiple arms of the immune system. Preliminary studies of targeting the vascular endothelial growth factor (VEGF) receptor tyrosine kinases with our vector platform indicated potent anti-tumor effects in an aggressive syngeneic glioma model in hICAM-1 transgenic mice.
The Aims of this project are to test CAV21 vaccine vectors against VEGF receptors 1 and 2 and evaluate the immunologic response and its effects on tumor growth, metastasis and angiogenesis.
Tumor growth and invasion correlates with activation of regulatory pathways that activate sprouting of blood vessels supplying the tumor with nutrients. We are testing a new type of vaccine based on a common cold- causing virus targeting these pathways. We will evaluate our immunization technology in a novel animal model for the common cold.
