Targeting of liver tumors by viroimmunotherapy and molecular retargeting of virus-neutralizing antibodies

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Oncolytic viruses are promising agents to promote the release and cross-presentation of tumor antigens, as well as to immune-activate tumors for subsequent checkpoint inhibition. However, oncolytic viruses are potent inducers of neutralizing antibodies which severely limit viral spread and therapeutic efficacy. In previous works, we have developed a molecular strategy to redirect these antiviral antibodies against tumors to fully exploit this virus-induced immunotherapeutic potential. To achieve such retargeting of neutralizing antibodies (nAb-retargeting) we established bispecific adapter molecules which bind adenovirus-specific antibodies and facilitate their binding to a molecular target on the surface of tumor cells. In adenovirus pre-challenged, tumor-bearing mice, systemic application of these bispecific adapter molecules inhibited tumor growth and prolonged survival. nAb-retargeting enhanced the antitumor effect of virotherapy and facilitated long-term cure when combined with PD-1/PD-L1 checkpoint inhibition. Moreover, nAb-retargeting significantly prolonged survival in a murine model with electroporation-induced, transgenic liver cancer. Based on these previous results, we want to study in the present project the molecular mechanisms of nAb-retargeting in liver cancer and want to evaluate the potential of this intervention to immunoactivate liver tumors for administration of checkpoint inhibitors. After treatment with virotherapy and adapter proteins for nAb-retargeting, the immune cell composition (TILs, NK cells, macrophages and other myeloid cells) in tumor tissue will be analysed in subcutaneous and electroporation-induced models of liver cancer. Next, we want to compare virotherapy and nAb-retargeting with repeated application of virotherapy as the current standard protocol in clinical studies. We will analyse the adaptation of the tumor microenvironment to these treatments and its consequences on the balance of antitumoral/antiviral immune responses. Furthermore, we want to investigate the effect of virotherapy and nAb-retargeting on antigen cross presentation and T cell priming in liver tumors with β-catenin-mediated immune dysfunction. Finally, we want to assess virotherapy and nAb-retargeting together with established and novel, alternative checkpoint targets such as TIGIT or CD96 in tumors in the immunosuppressive context of liver fibrosis. These studies will reveal the therapeutic potential of virotherapy and nAb-retargeting to effectively immunoactivate liver cancer for checkpoint inhibition.