OZR back-ip mandate: Fighting fire with fire: using oncolytic viruses to selectively target complement inhibition in tumor cells in order to alleviate immune suppression

Protection of host cells against complement-mediated lysis is an important mechanism of immune tolerance. In many types of cancer, complement regulatory proteins (CRPs) are upregulated and expression is correlated with clinical outcome. Downregulation of CRPs, especially CD59, the main inhibitor of formation of the membrane attack complex (MAC), was shown to sensitize tumor cells to complement dependent cytotoxicity (CDC). Oncolytic viruses (OVs) can specifically replicate in tumor cells. This results in tumor cell lysis and the induction of tumor-specific immune responses via the release of tumor-specific antigens (TAAs) as well as activation signals. This tumor-specific replication of OVs offers the possibility to selectively deliver payloads within the tumor. In this project, we wish to investigate whether selective CD59 downregulation on tumor cells enhances their sensitivity to CDC and whether this type of cell death is immunogenic. In a next stage, we will use modified OVs expressing a CRISPR/Cas9 system, to downregulate or block CD59. We hypothesize that the combined activity of CDC and OV-mediated lysis will enhance the extent of ICD, thus anti-tumor immune responses. Finally, we will combine anti-CD59 modified OVs with checkpoint inhibiting antibodies against PD-L1, most of which have an IgG1 isotype. We hypothesize that they not only sensitize the tumor to T cells but will also significantly enhance the levels of CDC when CD59 is downregulated or inhibited.