Abstract B175: Semliki Forest virus-mediated oncolytic immunotherapy in mouse GL261 glioblastoma model

Abstract

Glioblastoma (GBM) is a devastating cancer of the central nervous system with no cure currently available. Oncolytic virotherapy with viruses that infect and destroy cancer cells provides a novel promising candidate therapy. We have previously shown that Semliki Forest virus (SFV) has therapeutic potency against orthotopic xenograft and syngeneic glioma models in mice. Here we show that SFV-infected cancer cells undergo immunogenic apoptosis, which triggers phagocytosis and maturation in co-cultured dendritic cells. SFV-killed GL261 mouse GBM cell lysate was also able to induce protective antitumor immune response in syngeneic mouse model, indicating that SFV oncolysis is immunogenic in vivo. By introducing mutations into the viral genome we have been able to produce a novel SFV clone which shows notably enhanced oncolytic potency in GL261 cells. As compared to the wild-type virus, the mutated SFV replicates faster and induces significantly stronger cytopathic effect. Robust viral replication and cytopathic effect were detected despite of activated type-I interferon signaling in the infected cells. This suggests that the enhanced SFV has increased resistance to antiviral response in mouse GBM cells. Viral proteins were detected by immunohistochemistry in orthotopic GL261 tumors after intratumoral injection of the mutated SFV virus. This provides evidence that the enhanced SFV is able to replicate in GL261 tumors in the face of antiviral in vivo microenvironment. Unwanted SFV replication in healthy brain cells can be inhibited by microRNA-mediated de-targeting. Taken together, the results indicate that oncolytic virotherapy with SFV can trigger antitumor immune responses, and support that SFV is a potent new candidate for oncolytic immunotherapy of GBM. These findings pave way for future clinical trials with oncolytic SFV. Citation Format: Miika Martikainen, Di Yu, Mohanraj Ramachandran, Grammatiki Fotaki, Minttu-Maria Martikainen, Andres Merits, Magnus Essand. Semliki Forest virus-mediated oncolytic immunotherapy in mouse GL261 glioblastoma model [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B175.