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Introduction: HGG and DIPG represent highly aggressive CNS malignancies with mortality rates matching disease incidence. Treatment options for these diseases are limited once conventional therapy has failed, indicating a pressing need for more efficient strategies. OVT is a promising new approach in cancer research, which uses viral agents to specifically target tumor cells. So far, the oncolytic features of several OVs have been shown on GBM cell lines and in xenotransplant models. OVT has not been previously investigated in the treatment of DIPG. Likewise, orthotopic glioma studies in immunocompetent animals are lacking. Given the recent hypothesis that the host immune system could play a crucial role in the efficacy of the therapy, these studies are of vital importance.Methods and results: Here we investigated NDV virotherapy in the orthotopic, syngeneic murine GL261 HGG model. GL261 cells were sensitive to NDV-induced CPE in vitro. In vivo, NDV treatment significantly prolonged median survival and 50% of animals were cured long-term. This therapeutic effect was largely lost in immunodeficient mice (i.e. Rag2-/-), suggesting important immune involvement. We demonstrated induction of ICD in GL261 cells after NDV infection, comprising calreticulin surface exposure, release of HMGB1 and increased PMEL17 cancer antigen expression. Uniquely, we found absence of secreted ATP. NDV-induced ICD occurred independently of caspase signaling and was blocked by Necrostatin-1, suggesting the contribution of necroptosis. Autophagy induction following NDV infection of GL261 cells was demonstrated as well. In vivo, elevated infiltration of IFN-γ+ T cells was observed in NDV-treated tumors, along with reduced accumulation of MDSCs. The importance of this activated T cell fraction was demonstrated in CD8+ T cell depleted animals, where NDV virotherapy could prolong overall survival slightly, but failed to induce any long-term cure. We revealed the presence of a T cell fraction specifically responding to GL261 after OVT. Secondary tumor induction with GL261 cells or LLC cells in mice surviving long-term after treatment, further demonstrated the induction of a long-term, tumor-specific immunological memory response. Finally, we demonstrated a potential for DC vaccination during ongoing virus-induced immune reactivity, using DCs stimulated with NDV. Further investigations into this combinatorial approach are currently ongoing. Human primary DIPG cells were highly sensitive to NDV-induced CPE in vitro. In an in vivo DIPG xenotransplant model NDV virotherapy significantly prolonged median survival of treated animals as compared to untreated controls. In depth exploration of the oncolytic mechanisms of NDV in the treatment of DIPG is part of our ongoing work.Conclusion: In a murine orthotopic glioma model we show that the therapeutic effect of NDV virotherapy relies mainly on the induction of ICD in the tumor cells, which primes adaptive antitumor immunity.