Potential induction of protective anti-tumor immune response in cancer patients by oncolytic viruses containing the GGTA1 gene.

Oncolytic-viruses (OV) decrease tumor-mass but are less successful in eliciting long-term protective immune-response against tumor-antigens (TAs), due to poor uptake of tumor-cells by antigen-presenting-cells (APCs). It is postulated that this anti-tumor immune-response may greatly increase with OV containing the GGTA1-gene (OV-GT). GGTA1 encodes α1,3galactosyltransferase that synthesizes α-gal epitopes which bind the abundant human natural anti-Gal antibody. Tumor-cells infected with OV-GT present α-gal epitopes and bind the anti-Gal antibody. This antigen/antibody interaction activates the complement-system which mediates killing of tumor-cells presenting α-gal epitopes. The generated complement cleavage peptides C5a and C3a byproducts chemotactically recruit APCs. These APCs extensively phagocytose anti-Gal opsonized tumor-cells, following binding of the antibody's Fc portion to Fc-receptors on the APCs. The APCs transport TAs of internalized tumor-cells to lymph-nodes, process and present peptides of the processed TAs. These TA peptides activate TA specific T-cells including cytotoxic T-cells (CTL). Activated CTL proliferate, circulate and kill metastatic tumor-cells presenting TAs. It is suggested that Newcastle-disease-virus, used as an effective OV-GT (NDV-GT) mediates by this mechanism the observed complete elimination of hepatic-cell carcinoma metastases in cynomolgus monkeys. Furthermore, NDV-GT treated cancer-patients with advanced-disease demonstrated 90 % response of partial-remission, stable-disease, and one complete-remission. These findings suggest that the GGTA1-gene within various OV amplifies their therapeutic efficacy by converting infected tumor-cells into a therapeutic cancer vaccine.