Oncolytic Vaccinia Virus for the Treatment of Peritoneal Carcinomatosis: Combination with Chemotherapy and Targeted Radiotherapy

Oncolytic viruses (OVs) represent a novel class of cancer biotherapeutics currently under clinical development for treatment of a range of malignancies. OVs are ideal candidates for treatment of peritoneal carcinomatosis (PC) due to their high tumour specificity, excellent safety profile and suitability for peritoneal delivery. OVs are unlikely to be delivered alone but rather as part of a combination therapy regimen. The research presented in this thesis provides two examples of novel combination treatment strategies for improving oncolytic VV treatment of colorectal PC. Delivered as a monotherapy, vvDD efficacy was associated with mice that had well-vascularized and highly proliferative tumours. When combined with first-line colorectal cancer chemotherapy drugs, oxaliplatin and irinotecan (CPT-11), we observed synergistic improvements in in vitro tumour cell death and improved in vivo survival in tumour-bearing mice (with CPT-11). Synergy was attributed to sensitization of cells to drug treatment due to VV-induced S-phase arrest. In addition to combinations with chemotherapy, we examined the use of VV-mediated somatostatin receptor (SSTR) gene transfer using the radiolabeled somatostatin analogue 177Lu-DOTATOC. vvDD-SSTR led to tumour-specific accumulation of 177Lu-DOTATOC with minimal effects on normal tissue biodistribution in a xenograft model of colorectal PC. Radiovirotherapy was well tolerated and significantly improved survival over monotherapy. Our findings could have important implications for the design of future VV clinical trials and the treatment of colorectal PC. The proposed mechanism of synergy between vvDD and CPT-11 suggests that this combination therapy could represent a treatment option for patients with chemoresistant disease. Radiovirotherapy has wider potential applicability; any VV susceptible tumour could be made a target of SSTR-directed therapy. Continued investigation of the mechanisms of interaction between these treatment modalities will provide a better understanding of potential improvements to therapy delivery as well as the clinical setting in which they have the greatest impact.Ph.D