Abstract
In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor 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 antitumor immune response generated by oncolytic reovirus. In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after 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 after treatment with reovirus (intratumoral), sunitinib, or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation. Reovirus-mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor-specific CD8+ IFNγ-producing cells. Coadministration 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 rechallenge. Similar results were observed for KLN205 tumor-bearing mice, highlighting the potential broad applicability of this approach. The 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. Clin Cancer Res; 22(23); 5839-50. ©2016 AACR.
Highlights
Despite the improvements in progression-free (PFS) and overall survival (OS) associated with the use of targeted therapy, metastatic renal cell carcinoma remains an incurable disease
Reovirus replicates in human and murine renal cell carcinoma (RCC) cell lines resulting in oncolysis, chemokine production, and synergistic cytotoxicity when combined with sunitinib
Reovirus has been demonstrated to initiate innate immune responses characterized by the production of proinflammatory chemokines including RANTES, MIP-1-a, MCP-1, KC, IP-10, and MIG across a variety of melanoma and prostate cancer cell lines in addition to its direct oncolytic effects [14, 17]
Summary
Despite the improvements in progression-free (PFS) and overall survival (OS) associated with the use of targeted therapy, metastatic renal cell carcinoma (mRCC) remains an incurable disease. With a five-year survival rate of less than 10%, this malignancy remains a significant health issue [1]. The need for the development of novel therapeutic strategies for this disease is obvious. A multi-tyrosine kinase inhibitor targeting VEGFR, PDGFR, C-KIT, RET, CSF-1R, and FLT-3 is currently a first-line therapy for mRCC [2]. While this drug has historically been associated with potent antiangiogenic activity, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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