Oncolytic Viral Therapy for Glioma by Recombinant Sindbis Virus

SIMPLE SUMMARY: Gliomas account for 27% of all primary central nervous system tumors and have a highly aggressive growth pattern, leading most patients to be insensitive to conventional treatment. Viotherapy as a progressive therapeutic tool may be beneficial to improve the outcome of brain tumor treatment. However, the viruses used for glioma treatment at this stage are mostly limited to a few engineered replication-free defective viruses. In this study, we provide a replication-competent sindbis virus as a glioma treatment that, when combined with cytokines, is effective in slowing glioma progression both by intratumoral injection and systemic administration. This provides a promising concept for the treatment of glioma and also provides valuable data on the safety of using replicable sindbis virus as a glioma-killing agent. ABSTRACT: Background: The characteristics of glioblastoma, such as drug resistance during treatment, short patient survival, and high recurrence rates, have made patients with glioblastoma more likely to benefit from oncolytic therapy. Methods: In this study, we investigated the safety of the sindbis virus by injecting virus intravenously and intracranially in mice and evaluated the therapeutic effect of the virus carrying different combinations of IL-12, IL-7, and GM-CSF on glioma in a glioma-bearing mouse model. Results: SINV was autologously eliminated from the serum and organs as well as from neural networks after entering mice. Furthermore, SINV was restricted to the injection site in the tree shrew brain and did not spread throughout the whole brain. In addition, we found that SINV-induced apoptosis in conjunction with the stimulation of the immune system by tumor-killing cytokines substantially suppressed tumor development. It is worth mentioning that SINV carrying IL-7 and IL-12 had the most notable glioma-killing effect. Furthermore, in an intracranial glioma model, SINV containing IL-7 and IL-12 effectively prolonged the survival time of mice and inhibited glioma progression. Conclusions: These results suggest that SINV has a significant safety profile as an oncolytic virus and that combining SINV with cytokines is an efficient treatment option for malignant gliomas.