Purpose: Oncolytic viruses (OV) are attractive for use against multiple tumours given their ability to prime therapeutic immune responses in addition to their direct cytotoxic effects. We investigated the utility of reovirus, an OV currently in phase III clinical trials, as a novel immunotherapeutic against renal cell (RCC), non small cell lung (NSCLC) and breast carcinomas (BrCa) as both a monotherapy and in combination with sunitinib, a first line metastatic RCC agent. In addition the utility of adding an immune checkpoint inhibitor was investigated.
Experimental Design: In-vitro, cytotoxicity, viral replication and chemokine production were assessed in a panel of human and murine cancer cell lines following exposure to reovirus, sunitinib or their combination. In-vivo, RENCA (murine renal cell carcinoma) cells were implanted subcutaneously into female balb/c mice to establish a syngeneic immunocompetent model of RCC. Tumor growth and overall survival were assessed following treatment with reovirus, sunitinib or their combination. IFN-γ, myeloid-derived suppressor cells (MDSC), and protective immunity were assessed by ELISA, flow cytometry (Gr1+/CD11b+) and adoptive transfer experiments, respectively. PDL-1 and PD-1 expression on both tumour and immune cells were assayed.
Results: In vitro, exposure of RCC cell lines to reovirus resulted in an inflammatory cytotoxic response that was augmented through combination with sunitinib. In vivo, reovirus significantly reduced RENCA tumor burden and generated an anti-tumor immune response that was augmented by sunitinib. Combinations with sunitinib also lead to a decrease in myeloid-derived suppressor cells (MDSC) and resulted in improved overall survival and enhanced protective immunity. Preliminary results in NSCLC and BrCa are suggestive that this strategy maybe applicable to many cancer histologies. Both PDL-1 and PD-1 expression were up regulated by RV (similar to IFN gamma) in the majority of cell lines tested suggesting a potential role for checkpoint blockade (CB).
Conclusions: Reovirus has both direct oncolytic and immunotherapeutic activity against RCC, which is augmented through combination with sunitinib. The role of immune CB is ongoing. These proof-of-principle investigations provide clear rationale to investigate RV/sunitinib/immune CB as a promising approach for early phase clinical trials as a novel treatment strategy for cancer.
Citation Format: Ahmed Mostafa, Kathy Gratton, Keith A. Lawson, Zhong-Qiao Shi, Chandini Thirukkumaran, Don G. Morris. PDL-1 blockade and Sunitinib enhance the efficiency of oncolytic viral therapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A12.
- ©2015 American Association for Cancer Research.