419. Efficacy of Rambo for Sarcoma Therapy

Abstract

Soft Tissue Sarcoma (STS), a cancer which forms in the connective tissue, requires aggressive treatment. Metastatic soft tissue sarcomas are associated with a median prognosis of about twelve months accompanied frequently with many signs and symptoms leading to a poor quality of life. These tumors frequently have angiogenic properties. Angiogenesis is responsible for the formation of new blood vessels and is associated with local progression and increased metastatic disease. Strategies that work to block angiogenesis are currently being investigated as a treatment for STS. Oncolytic virus therapy is a novel treatment strategy that utilizes modified viruses to specifically replicate and lyse cancer cells. The combination of angiogenesis inhibitors with oncolytic virus treatment has not been tested for STS. Here we tested the effect of combining oncolytic viral therapy with antiangiogenic gene therapy. RAMBO is a HSV-1 derived oncolytic virus that codes for the production of Vstat120, a gene with potent antiangiogenic effects. We have tested a panel of sarcoma cells and shown effective infection and lysis of these cells by RAMBO and HSVQ-1 in vitro. In vivo, we compared the antitumor efficacy of RAMBO and HSVQ-1 against sarcoma tumors grown in mice. Briefly, mice were implanted with 150-300mm3 A673 sarcoma tumors were injected with a PBS, HSVQ-1, or RAMBO (5.5×106 pfu). Mice were followed for tumor size over a period of time. Tumor volumes over time were logarithm (base 2) transformed for variance stabilization. The linear mixed model was used to compare the three groups while accounting for the variance-covariance structure due to repeated measures at different days from the same mouse. Statistically significant improvement in antitumor efficacy was observed in RAMBO treated tumors, compared to HSVQ-1 and control. H&E staining of tumor tissue reveals large areas of necrosis in RAMBO treated tumors. RAMBO and its inherent antiangiogenic gene therapy demonstrated significant efficacy in these sarcoma models and further investigations are underway with combination therapeutic strategies.