Periodic Reporting for period 1 - AVITAG (Alphaviral Immunotherapy against Glioblastoma)
Reporting period: 2016-05-01 to 2018-04-30
Among the emerging new cancer therapies is oncolytic virotherapy. This therapy is based on use of viruses that selectively replicate in cancer cells. The mode of action consists of viral replication-caused tumour cell destruction (oncolysis) which is accompanied by immune system attack against the infected cells. In the optimal scenario viral infection in the tumour cells would also lead to release factors (Tumour associated antigens, damage-associated molecular patterns, inflammatory cytokines, chemokines etc.) needed to educate the patient’s immune system to recognize and destroy also non-infected cancer cells. This would lead to persistent systemic immunity and complete eradication of otherwise untreatable cancer.
In this project, PhD Miika Martikainen and collaborators aimed to develop oncolytic virotherapy against GBM using an alphavirus called Semliki Forest virus (SFV). The project was based on earlier results in Martikainen’s PhD thesis that indicate SFV as a potent oncolytic agent against GBM.
Our results indicate that SFV-mediated oncolysis is immunogenic and capable of inducing protective activation of the immune system against GBM. This was evident in cell culture conditions, where SFV-infected GBM cells could induce phagocytosis and maturation in dendritic cells. SFV-killed cell lysate was also shown to trigger protective immune response in mouse GBM model. The immunostimulatory properties of SFV virotherapy suggests that synergistic effects could be achieved by combining SFV therapy with other forms of immunotherapy. Although we saw no added benefit of combining SFV with dendritic cell vaccination or heterologous prime boost strategy, the results clearly support that SFV has potential as immunotherapeutic agent against GBM.
Another important aspect of the project was to increase oncolytic potency of the currently available SFV constructs. Notably, we were able to significantly enhance SFV replication in GBM cells by introducing targeted mutations into the viral genome. The enhanced SFV virus was able to reach glioma cells in the brain upon intraperitoneal injection. This is important indication that systemically administered SFV can reach otherwise hard-to-reach tumour sites.