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Alphaviral Immunotherapy against Glioblastoma

Periodic Reporting for period 1 - AVITAG (Alphaviral Immunotherapy against Glioblastoma)

Reporting period: 2016-05-01 to 2018-04-30

Glioblastoma (GBM) is the most frequent and most severe type of primary brain tumour, with incidence of 3-4/100 000 persons. GBM is associated with strong immunosuppression, invasiveness and recurrence after therapy. The current standard care for GBM is maximal resection of the tumour combined with radiation therapy and chemotherapy with temozolimide. Despite this intervention, GBMs remain 100% fatal with median survival of only 12 - 15 months. Consequently, there is an urgent need for novel effective therapy.

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.
The fellowship was conducted in Uppsala University during 01/05/2016 - 30/04/2018 in the Gene, Cell and Immunotherapy of Cancer -research group led by Professor Magnus Essand, in collaboration with Professors Andres Merits (university of Tartu, Estonia) and Thomas Tüting (Otto Von Guericke University Magdeburg, Germany). During the fellowship we worked to improve upon earlier results by carrying out comprehensive analysis of SFV-induced cell death and evaluating feasibility of immunostimulatory combination therapies.

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.
The aim of research in Professor Magnus Essand lab is advancing translational cancer immunotherapy, focusing on development of oncolytic viruses, CAR T-cells and dendritic cell-based vaccines. During the past year, immunotherapy has become the current state of art in cancer therapy. Our results support that oncolytic virotherapy with SFV can trigger anti-tumour immune responses. Thereby oncolytic SFV virotherapy can be considered to also be a form of cancer immunotherapy. We are confident that further development in the SFV construct design can lead to a significant breakthrough in the oncolytic immunotherapy of GBM.
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