YB-1 based virotherapy

Many solid tumors, including Ewing sarcomas and head and neck cancers, are characterized by immunosuppressive properties that severely limit the use of immunotherapies in their current form. Oncolytic virotherapy is a novel approach in the fight against cancer and is currently being investigated for its efficacy in clinical trials, in addition to the approvals that have already been granted. Oncolytic virotherapy refers to the use of specifically modified viruses that can only multiply in tumor cells and thus kill them. Killing the tumor cells not only reduces the local tumor volume, but also induces systemic anti-tumor effects. Thus, virotherapy represents a solution for overcoming the immunosuppressive nature of solid tumors and is very well suited as a combination partner with established therapies. This research project aims to investigate details of virus replication and the induced immune response in an innovative therapeutic approach. For this, the oncolytic adenovirus XVir-N-31 is combined with two targeted therapy options. One option, so- called CDK4/6 inhibitors, interferes with the cell cycle and thus prevents the growth of cancer cells. The other option is BET inhibitors, which prevent the expression of oncogenes. Both therapies induce an immunologically favorable reorganization of solid tumors as monotherapies and enhance the oncolytic effect of XVir-N-31. Thereby, this innovative therapeutic approach has the potential to overcome the immunosuppressive hurdles of solid tumors. Inasmuch as both inhibitors alter the tumor cells at the molecular level, the aim of this project is to elucidate which changes lead to the enhancement of the oncolytic potential of XVir-N-31. Based on existing data, the focus of our investigations is on the immunological aspects in vivo as well as on the regulation of general factors involved in gene expression. The results obtained are highly relevant for future translational research projects and will provide new insights into the regulation of adenoviral transcription programs. As the therapeutic effect of oncolytic viruses, such as XVir-N-31, is mainly due to their immunostimulatory effects, we are firmly convinced that this innovative combination approach is of high clinical relevance.