Browsing by Author "Zemp, Franz Joseph"

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    Myxoma Virus Therapy of Malignant Gliomas in Murine Syngeneic Models: Translating Barriers to Therapy
    (2013-09-13) Zemp, Franz Joseph; Forsyth, Peter; Yong, V. Wee
    High grade glioma has an almost universally fatal outcome. Failure of current treatment modalities has prompted the investigation into non-traditional therapies. Oncolytic virus therapy entails the use of replication competent viruses that selectively infect, replicate and kill cancer cells. This multi-modal therapy can function to directly kill cancer cells, stimulate anti-tumour immune responses, and be engineered to express additional anti-tumour activities. Despite promising preclinical studies in xenograft models, clinical trials have demonstrated no overwhelming treatment responses. Interestingly, syngeneic glioma models have shown results more typical of what was seen in the clinic. This study was undertaken to identify the potential immune-effectors mediating Myxoma virus (MYXV) clearance in immunocompetent mouse models. MYXV is a rabbit-specific poxvirus that has oncolytic properties in cancer cell lines, having previously been shown to ‘cure’ human xenograft models. We found that syngeneic murine glioma lines derived from Nf1+/-Trp53+/- mice formed aggressive, gliosarcoma-like tumours in the brains of C57Bl/6 mice, but MYXV administration resulted in a very transient infection and no treatment efficacy. Further, a new syngeneic glioma model was created through culturing spontaneous gliomas from these mice as neurospheres. These lines displayed stem cell markers and produce highly invasive gliomas when grafted into the brains of immunocompetent C57Bl/6 mice. We hypothesized that Type-I interferon (IFNα/β), could be playing a role in this resistance. However, it was found that MYXV treatment did not elicit an IFNα/β response in these glioma lines in vitro or in vivo. Further, engineered ablation of IFNα/β signalling in the glioma in vivo had no change in treatment outcome. Immunophenotyping the glioma microenvironment found these gliomas were heavily infiltrated with microglia and macrophages, just as has been shown in human patients. Ablation of tumour-resident macrophages, not treatment-recruited macrophages, resulted in a significant increase in viral infection in the tumours that resulted in a mild survival advantage; however, the virus was still rapidly cleared in these animals. NK and T cell populations were also recruited to the tumour. Interestingly, ablation of both these populations, but not either one alone, resulted in a robust, durable infection in the tumour that resulted in survival benefit.