Assessment of YB-1 Dependent Oncolytic Adenovirus-Based Glioma-Virotherapy on Cellular Immune Responses

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Glioblastoma (GBM) is the most common malignant brain tumors. Although surgical resection, radiotherapy as well as chemotherapy prolong survival to 12-15 months, new therapeutic strategies areneeded. Oncolytic virotherapy is an upcoming therapy strategy for cancer treatment. A variety of preclinical and clinical trials have shown that adenoviruses can be used as potent agents in the treatment of cancer. In addition, recent reports have presented strong evidence for a significant role of oncolytic virotherapy in the activation of anti-tumor immune responses. With regard to oncolytic adenoviruses (OAV) we have demonstrated that YB-1 is a potent factor we have used to develop YB-1-dependent OAVs (YB-1-OAV) showing the capacity of tumor-selective replication and convincing oncolytic property in different murine xenograft tumor models. In recent years we focused on the optimization of viral properties to increase its immunogenic activity to elicit a potent antitumor immune response. Our newly developed YB-1-OAVs facilitate a highly immunogenic kind of cell death. This is an advantage to virothera-peutic strategies based on Adeno-WT-derived OAV which evolutionary inhibit immune response. However, little is known about the effect of OAV mediated cell killing and its specific effects on the immune system in vitro and in vivo. YB-1 OAVs give us the unique opportunity to investigate the role of the immune system to elicit a potent antitumor immune response. Therefore, in the planned project we want to investigate the anti-tumoral immune activation by YB-1-OAV based virotherapy and ist impact on the therapeutic efficacy in vitro in human GBM specimen and in an in vivo humanized murine GBM model. Combined viro-/immunotherapy for GBM, even after enhancement by immunogenic YB-1-OAVs, might not yet achieved its full potential. One reason is that glioma have developed an array of strategies to evade and suppress antitumor immune responses. PD-1 is an immune checkpoint receptor that is expressed on lymphocytes and has been implicated to be a mediator of immune suppression in a variety of tumors, including GBM. Binding of PD-1 to its ligand PD-L1, which is expressed on GBM cells, induces exhaustion of tumor infiltrating T cells. Blocking this interaction has been shown to enhance the immune response towards GBM and to prolongate, in combination with radiotherapy, median survival of GBM bearing mice. Therefore, in a second step it is planned to combine YB1-OAV-virotherapy with the blockade of PD-1/PD-L1 signaling (by either applying Nivolumab or by virus-based expressing of a PD-L1 neutralizing anibody directly in infected glioma cells in the tumor micromilieu, and to analyze whether this will further enhance the therapeutic effects of anti-GBM virotherapy. Final goal is the development of a novel therapy for recurrent GBM by combining oncoviro- and immunoherapeutic approaches.