Viroimmunotherapy for Renal Cell Carcinoma

Purpose:In addition to their direct cytopathic effects, oncolytic viruses are capable of priming anti-tumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the anti-tumor immune response generated by oncolytic reovirus. Experimental Design:In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines following exposure to reovirus, sunitinib or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses following treatment with reovirus (intra-tumoral), sunitinib or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation Results:Reovirus mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive anti-tumor immune response evidenced by increased numbers of tumor-specific CD8+ IFN- producing cells. Co-administration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells and the establishment of protective immunity upon tumor re-challenge. Similar results were observed for KLN205 tumor bearing mice, highlighting the potential broad applicability of this approach. ConclusionsThe ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC.

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