Science and Technology Platform Program for Advanced Biological Medicine


Study of next-generation oncolytic vaccinia virus for cancer virotherapy

<Project Leader> Takafumi Nakamura

Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapeutics, School of Medicine, Tottori University Faculty of Medicine

Takafumi Nakamura

Oncolytic virus (OV) are promising therapeutic agents for cancer and are currently under clinical investigation. The virotherapy is novel strategy that viruses infect and replicate within tumor cells, and directly lyse and kill them. Following this, OV can function as a ‘kick-start’ for anti-tumor immunity (Fig. 1). Because of these different modes of action, cross-resistance, which occurs after standard chemotherapy or radiotherapy, is much less likely to develop with virotherapy. We have genetically engineered different kinds of viruses and used as an oncolytic virus for cancer virotherapy. Recently, we focus on highly attenuated vaccinia virus (VV) which was used for smallpox vaccine without serious side effects in human. Because VV can not only have potent oncolytic activity for various kinds of tumors but also deliver therapeutic genes into tumors as a vector.
So far, we demonstrated that the therapeutic index would be enhanced by stricter tumor-specific viral replication, weaker viral antigenicity and stronger anti-tumor immunity via expressions of cytokines. Deletion of both VGF and O1 genes inhibited pathogenic viral replication in normal cells without impairing therapeutic replication in tumor cells. Simultaneously, partial deletion of antigenic glycoprotein B5R enhanced immune escape capacity by vaccinia virus while preserving its oncolytic function (Molecular Therapy Oncolytics 14: 159-171, 2019). Furthermore, expression of two genes IL-7 and IL-12 augmented anti-tumor activity of oncolytic vaccinia virus via inducing potent and durable anti-tumor immune responses following viral oncolysis. (Science Translational Medicine 12: eaax7992, 2020). On the other hand, the efficient viral replication and spread plays a crucial role in the therapeutic outcome. However, little is known about the influence of host factors on the viral replication and spread. To address this question, long non-coding RNA urothelial carcinoma-associated 1 (UCA1) has been identified and evaluated using clinical samples from cancer patients as potential biomarker of therapeutic response to oncolytic VV (Molecular Therapy Oncolytics 13: 35–48, 2019).
In the study, we are developing novel technologies for 1) stronger oncolytic potency, 2) optimized induction of antitumor immunity, 3) predictive biomarkers of therapeutic responses and 4) simple, rapid, and efficient virus production (Fig. 2). Taken together, we aim to establish next-generation oncolytic vaccinia virus for cancer virotherapy via combination of these novel technologies.

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