New data from an in vivo renal cell carcinoma (RCC) model show that boosting the antitumour immune response induced by an oncolytic reovirus through combination with sunitinib results in improved tumour control and protective antitumour immunity, according to a report in Clinical Cancer Research.

Oncolytic viruses are being investigated for the treatment of various cancers but results suggest that viruses alone often do not provide sufficient anticancer efficacy. Building on accumulating evidence, new strategies are focussed on utilizing the antitumour immunogenic effects inherent in the cytopathic mode of action of these agents.

In a recently published study, researchers from the University of Calgary, Alberta, Canada, investigated a combination treatment consisting of an oncolytic reovirus and the tyrosine kinase inhibitor sunitinib. To enable testing of immune responses, the team used an immunocompetent syngeneic RCC mouse model, established using RENCA cells.

Credit: P. Morgan/NPG

In vitro, the researchers found that infection of a range of human RCC cell lines resulted in widespread cell death and virus progeny production. Results of experiments in RENCA cells were similar and also showed production of proinflammatory cytokines, such as MCP-1 and IP-10. Combination treatment of RENCA cells with reovirus and sunitinib showed synergistic effects for specific dose concentrations.

In subsequent in vivo studies using the syngeneic RENCA RCC model, the team found that treatment with the combination of reovirus and sunitinib resulted in a significantly increased reduction in tumour volume compared with reovirus alone and prolonged survival compared with either agent alone.

Investigation of immune responses revealed that IFNγ production after stimulation with reovirus-infected RENCA cells was fourfold higher in CD8+ splenocytes isolated from mice that had received reovirus and sunitinib compared with those from mice treated with reovirus only. On a cellular level, depletion of CD8+ cells in vivo abrogated the survival benefit conferred by the combination treatment; addition of sunitinib to reovirus treatment seemed to reverse reovirus-induced accumulation of immunosuppressive immune cells, such as intratumoural regulatory T cells. When mice that had previously had complete responses to combination treatment were rechallenged with RENCA cells no tumour growth was observed, suggesting establishment of protective immunity in these animals.

This study shows that augmentation of the immunotherapeutic effect of an oncolytic virus is feasible using an established small molecule inhibitor and that evaluation in a clinical setting might be warranted.