Enhancing the immunogenicity and antitumor efficacy of virotherapy by supplementing an oncolytic virus with checkpoint inhibition and immunological cell death inducers

In addition to being important pathogens, viruses can also acquire the capacity to kill tumor cells, without harming normal cells. Although these so-called oncolytic viruses (OVs) have been studied for several decades, their mechanisms of action are still elusive. In recent years, it has become clear that the antitumor effects of OVs not only hinges on direct killing effects, but that immunological mechanisms also play a cruicial role. Thus, the combination of dying cancer cells and viral components induces an inflammatory response, which evokes effector immune cells that help to remove the tumor. A cruicial determinant of the quality and quantity of this immune
response is the meachnism of cell death, which is induced by OVs. So far, not much is known about the cell death mechanisms induced by OVs. On the other hand more and more information is becoming available about the fact, that the type of cell death determines the antitumor immune responses. Therefore, in this project we want to examine, whether we can trigger specific cell
death modalities by modified OVs to obtain synergism and thus increase antitumor immune responses. Therefore, as a second objective we want to investigate whether combining OV therapy and moieties that specifically block inhibitory molecules leads to enhanced antitumor immune responses, that are preferentially targeted towards tumor cell specific mutations.