66. Recombinant Newcastle Disease Virus as an Oncolytic Therapy for Ovarian and Prostate Cancers

Newcastle disease virus (NDV) is a member of the Avulavirus genus in the Paramyxoviridae family. NDV selectively replicates in tumor cells due to defects in antiviral and apoptotic signalling. It is the oncolytic virus with the longest history of use in clinical trials with a proven safety record as a monotherapy due to its strong induction of antiviral responses in non-transformed mammalian cells. In addition to its direct oncolytic effect, NDV also activates both innate and adaptive immune responses and therefore has strong immunotherapeutic potential. To enhance the fusogenicity of the virus, the fusion protein of recombinant LaSota NDV (rNDV) was engineered to express a multibasic cleavage and activation site (rNDV/F3aa). This virus is highly fusogenic leading to the formation of large syncytia that allows for efficient intratumoral spread and increased lytic potential. While NDV has demonstrated efficacy in a number of different cancer models, including melanoma and hepatocellular carcinoma, little information about its efficacy in ovarian and prostate cancer is available. To this end, we evaluated the oncolytic potential of rNDV/F3aa expressing enhanced green fluorescent protein (GFP) in a panel of prostate and ovarian cancer cell lines using a resazurin dye-based cell viability assay. Infection with rNDV/F3aa-GFP at a range of MOIs significantly reduced the viability of these cancer cells in vitro, but had little effect on normal untransformed cells. To evaluate the efficacy of NDV in vivo, we used a well-established orthotopic mouse model of epithelial ovarian cancer and a syngeneic murine RM9 prostate carcinoma model. Intravenous delivery of 1×10^8 PFU of rNDV/F3aa-GFP to ovarian tumor-bearing mice resulted in a significant reduction in the primary tumor size and number of metastatic abdominal tumours. Furthermore, 50% of the mice had a complete loss of ascites, which is an accumulation of fluid in the abdomen, as a result of advanced stage ovarian cancer. The apparent decrease in secondary disease after treatment with rNDV/F3aa-GFP is particularly promising as it is the metastatic lesions that ultimately cause high morbidity and mortality in patients with advanced ovarian cancers. A pilot study in the RM9 prostate model revealed that rNDV/F3aa-GFP was able to replicate and spread within the tumor and neovasculature after intratumoral or intravenous delivery of 1×10^8 PFU. Studies to confirm these results, as well as to evaluate the ability of rNDV/F3aa-GFP to induce tumor regression and increase survival are currently underway. Taken together, these data suggest that NDV/F3aa is a promising oncolytic for further development as an anti-cancer agent for the treatment of prostate and ovarian cancers.