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Systemic reovirus therapy of metastatic cancer in immune-competent mice
Kensuke Hirasawa1, Sandra G Nishikawa, Kara L Norman
1Cancer Biology Research Group and Departments of Microbiology and Infectious Diseases, University of Calgary, School of Medicine, Calgary, Alberta, T2N 4N1 Canada.
Abstract:
The human reovirus is an oncolytic virus that specifically targets cancer cells with an activated Ras pathway. Because it is replication competent and highly specific for cancer cells, this virus has the potential to be an effective antimetastatic cancer agent through remote site delivery. In this study, we exploited the ability of reovirus to replicate in murine cells to test the efficacy of this virus in eliminating distal and/or metastatic tumors in immune-competent mice. We found that i.v. therapy with reovirus not only inhibited metastatic tumor growth but also led to a significant improvement in animal survival. Combining i.v. reovirus treatment with immune suppression (cyclosporine A or anti-CD4/anti-CD8 antibodies) resulted in further reduction in tumor size and a considerable prolongation in survival, compared with viral therapy alone. Combined therapy was also effective in overcoming a preexisting immunity to reovirus (a common occurrence in humans and thus a potential impediment to oncolytic effectiveness) to induce metastatic tumor regression. This is the first study to use systemic delivery of an oncolytic agent in conjunction with immune-suppressive drugs to effectively prolong animal survival. Altogether, our results suggest that i.v. reovirus therapy may present a feasible, novel alternative in the treatment of metastatic cancer in humans.
Insights
Intravenous reovirus therapy effectively inhibited metastatic cancer growth and improved survival in mice. Combining this oncolytic virus treatment with immune suppression further enhanced anti-tumor effects and overcame existing immunity.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Human reovirus is an oncolytic virus targeting cancer cells with activated Ras pathways.
- Replication-competent and cancer-specific viruses offer potential for antimetastatic therapy via systemic delivery.
Purpose of the Study:
- To evaluate the efficacy of intravenous reovirus therapy in eliminating distal and metastatic tumors in immune-competent mice.
- To assess the impact of combining reovirus therapy with immune suppression on tumor growth and animal survival.
Main Methods:
- Utilized the replication capability of reovirus in murine cells for therapeutic evaluation.
- Administered intravenous reovirus therapy, alone and in combination with immunosuppressive agents (cyclosporine A, anti-CD4/anti-CD8 antibodies).
- Assessed tumor size, metastatic tumor growth, and animal survival rates.
Main Results:
- Intravenous reovirus therapy significantly inhibited metastatic tumor growth and improved animal survival.
- Combined therapy with immune suppression led to greater tumor reduction and prolonged survival compared to reovirus alone.
- Combined therapy effectively overcame pre-existing anti-reovirus immunity, inducing metastatic tumor regression.
Conclusions:
- Systemic reovirus therapy, particularly when combined with immune suppression, demonstrates significant potential for treating metastatic cancer.
- This approach may overcome challenges posed by pre-existing immunity to oncolytic viruses in humans.
- Intravenous reovirus therapy represents a novel and feasible treatment strategy for human metastatic cancer.