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Abstract

Treatment-refractory tumors such as pancreatic ductal adenocarcinoma (PDAC) or head and neck squamous cell carcinoma (HNSCC) remain a major challenge in medical oncology and translational cancer research. Modern radiotherapy techniques are able to achieve maximal tumor damage while trying to limit off-target toxicity. Nevertheless, refractory tumors often show radioresistance. To achieve superior anti-tumor efficacy, this study investigates radiotherapy combined with virotherapy using oncolytic vaccine strain measles virus (MeV). Oncolytic MeVs feature an excellent safety profile and have shown first signs of anti-tumor efficacy in clinical trials. No cross-resistances of MeV with current therapeutic agents have been detected. They infect malignant cells as well as spread within tumors, leading to oncolysis of cancerous cells and induction of an immune response. Thus, MeV represents a promising modality for combination treatments. I hypothesize that the combination of radiotherapy and oncolytic MeV in a radiovirotherapy (RVTx) synergizes in terms of tumoricidal effects and induces a sustained anti-tumor immune response. I tested different dose regimens of radiation as well as oncolytic MeV in a panel of human HNSCC and PDAC cell lines in vitro. I assessed cell viability after RVTx treatment and could confirm synergism of RVTx in both tumor entities for specific treatment conditions. Further, I investigated possible mechanisms of action, focusing on the induction of immunogenic cell death (ICD), markers known for DNA damage and viral RNA sensing as well as downstream effects of innate immune activation. The combination treatment induced higher levels of the ICD markers high mobility group box 1 (HMGB1) and calreticulin (CALR) compared to each monotherapy. Further, interferon signaling was induced in RVTx, driven by virotherapy. I established an immunocompetent murine HNSCC model that is susceptible to MeV infection. In an in vivo pilot study using this model, I detected increased tumor infiltration of CD8+ T cells as well as virus-driven immunoreactivity in co-cultures of splenocytes and tumor cells after RVTx treatment. In two human ex vivo PDAC tumor models, I analyzed the therapeutic efficacy of RVTx. I could show viral spread in 3D spheroids. Further, RVTx induced virus-driven ICD and interferon-β release in patient-derived PDAC cultures. This study identified synergistic therapeutic regimens and provides the proof-of-concept for the induction of an anti-tumor immune response by RVTx. Insights into mechanisms of anti-tumor efficacy were gained in relevant preclinical models. Therefore, this project constitutes important steps towards the development and clinical translation of a state-of-the-art combination treatment modality to achieve sustained improvements for the therapy of refractory tumors.