A chimeric oncolytic rhabdovirus for the treatment of melanoma

Surgery, irradiation and chemotherapy, the classical treatment triad for non-hematologic cancers, generally fail in metastatic disease. Oncolytic viruses (OVs) have a completely different mode of action and thus should be effective when standard treatments fail. OVs preferentially replicate in and destroy cancer cells, additionally, they induce a local inflammation that can promote an antitumor immune response. One of the most potent OVs in vitro and in animal models is the vesicular stomatitis virus (VSV). However, VSV has two major shortcomings: primarily, VSV is neurotoxic, which has so far hindered clinical application. In addition, VSV rapidly induces neutralizing antibodies to the viral glycoprotein G, limiting the efficacy of repeated VSV applications. We have overcome both limitations by substituting the glycoprotein GP of the lymphocytic choriomeningitis virus (LCMV) for VSV G ([1] and Muik et al, in preparation). The resulting VSV-GP pseudotype virus is safer than VSV, being non-neurotoxic while retaining oncolytic potency. In addition, LCMV-GP does not readily induce neutralizing antibodies. The therapeutic effect of oncolytic VSV is the result of a complex interaction of the innate and adaptive immune response with direct viral cytotoxicity for cancer cells. Thus, the primary aim of the proposed project is to understand the complex interplay of the innate and adaptive immune system with oncolytic VSV-GP that cures murine melanoma. An in depth understanding of the interaction of oncolytic VSV-GP infection with the relevant immune effectors will allow the rational design of novel combination therapies that further enhance the efficacy of VSV-GP for cancer treatment.

Oncolytic viruses (OV) represent a promising therapeutic option to treat cancer. OVs selectively replicate in and thereby lyse tumor cells. In our study, we used a novel vesicular stomatitis virus (VSV)-derived oncolytic virus (VSV-GP), which does not induce vector-specific neutralizing antibody responses readily, thereby allowing repeated applications. We developed a treatment regimen by combining VSV-GP with DC vaccination, which significantly improved the disease outcome in a mouse melanoma model. We analyzed in detail the innate and adaptive immune mechanisms induced upon OV-DC combination therapy to find key players responsible for the treatment success. Killing of tumor cells by VSV-GP released tumor-associated antigens and provided danger signals, which in turn reduced the local immune-suppression in the tumor and boosted the tumor specific immune effectors. Thus our work provided further evidence that OVs, especially in combination with other immune therapies, provide an ideal tool for tumor immunotherapeutic regimen.