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Title: Newcastle disease virotherapy - a novel immunotherapeutic approach in the treatment of high-grade glioma
Other Titles: Newcastle disease virotherapie - een nieuwe vorm van immunotherapie voor de behandelig van hooggradig glioma
Authors: Koks, Carolien
Issue Date: 8-Dec-2014
Abstract: High-gradeglioma (HGG) and diffuse intrinsic pontine glioma (DIPG) represent highlyaggressive central nervous system malignancies with mortality rates matchingdisease incidence. Treatment options for these diseases are limited onceconventional therapy has failed, indicating a pressing need for more efficientstrategies. Oncolyticvirotherapy (OVT) is a promising new approach in cancer research, which usesviral agents to specifically target tumor cells. So far, the oncolytic featuresof several oncolytic viruses have been shown on glioblastoma cell lines and inxenotransplant models. OVT has not been previously investigated in thetreatment of DIPG. Likewise, orthotopic glioma studies in immunocompetentanimals are lacking. Given the recent hypothesis that the host immune systemcould play a crucial role in the efficacy of the therapy, these studies are ofvital importance. Here weinvestigated Newcastle disease virus (NDV) virotherapy in the orthotopic,syngeneic murine GL261 HGG model. GL261 cells were sensitive to NDV-induced cytopathiceffects in vitro. In vivo, NDV treatment significantlyprolonged median survival and 50% of animals were cured long-term. Thistherapeutic effect was largely lost in immunodeficient mice (i.e. Rag2-/-),suggesting important immune involvement. <span style="mso-ansi-language:EN-US" lang="EN-US">We demonstrated induction of immunogenic cell death in GL261 cells afterNDV infection, comprising calreticulin surface exposure, release of HMGB1 andincreased PMEL17 cancer antigen expression. Uniquely, we found absenceof secreted ATP. NDV-inducedimmunogenic cell death occurred independently of caspase signaling and wasblocked by Necrostatin-1, suggesting the contribution of necroptosis. Autophagyinduction following NDV infection of GL261 cells was demonstrated as well. <span style="mso-ansi-language:EN-US" lang="EN-US">In vivo,elevated infiltration of IFN-gamma<span style="mso-ansi-language:EN-US" lang="EN-US">+ T cellswas observed in NDV-treated tumors, along with reduced accumulation of immunosuppressivemyeloid derived suppressor cells. The importance of this activated T cellfraction was demonstrated in CD8+ T cell-depleted animals, where NDVvirotherapy could prolong overall survival slightly, but failed to induce anylong-term cure. We revealed the presence of a T cell fractionspecifically responding to GL261 after OVT. Secondary tumor induction withGL261 cells or LLC cells in mice surviving long-term after treatment, furtherdemonstrated the induction of a long-term, tumor-specific immunological memoryresponse. Finally, wedemonstrated a potential for dendritic cell vaccination during ongoingvirus-induced immune reactivity, using dendritic cells stimulated with NDV. Furtherinvestigations into this combinatorial approach are currently ongoing. Human primary DIPG cells were highlysensitive to NDV-induced cytopathic effects invitro. In an in vivo DIPGxenotransplant model NDV virotherapy significantly prolonged median survival oftreated animals as compared to untreated controls. In depth exploration of theoncolytic mechanisms of NDV in the treatment of DIPG is part of our ongoingwork. In conclusionwe have shown, in a murine orthotopic glioma model, that the therapeutic effectof NDV virotherapy relies mainly on the induction of immunogenic cell death inthe tumor cells, which primes adaptive antitumor immunity.<span style="mso-fareast-font-family:"Times New Roman";mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US;mso-fareast-language:NL-BE" lang="EN-US"><i style="mso-bidi-font-style:normal"><span style="mso-fareast-font-family:"Times New Roman";mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US;mso-fareast-language:NL-BE" lang="EN-US"><span style="mso-fareast-font-family:"Times New Roman";mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US;mso-fareast-language:NL-BE" lang="EN-US"><span style="mso-fareast-font-family:"Times New Roman";mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US;mso-fareast-language:NL-BE" lang="EN-US"><span 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Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Pediatric Immunology
Research Group Experimental Neurosurgery and Neuroanatomy

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