Telomerase-Specific Replication-Selective Virotherapy for Bone and Soft Tissue Sarcomas

INTRODUCTION: Bone and soft tissue sarcomas represent a small percentage of cancers worldwide; however, they are the third most children cancer in United States. Despite major advances in the treatment of advanced bone and soft tissue sarcomas such as the introduction of novel chemotherapy regimens, therapy fails in about one fourth of the patients. Therefore, to treat the patients with advanced primary bone and soft tissue sarcomas, a multidisciplinary approach is required. Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor, but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Furthermore, a Phase I clinical trial of OBP-301, which was conducted in the United States on patients with advanced solid tumors, indicated that OBP-301 is well tolerated by patients. Recent evidence suggests that non-epithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear if OBP-301 is cytopathic for non-epithelial malignant cells. However, some populations of tumor cells lack CAR expression, suggesting a requirement for the development of a novel antitumor therapy against CAR-negative tumor cells. We recently developed fiber-modified OBP-405, which can bind to integrin molecules (v3 and v5) and efficiently kill coxsackie adenovirus receptor (CAR)-negative tumor cells. In the present study, we first investigated the in vitro cytopathic efficacy of OBP-301 against 14 human bone and soft tissue sarcoma cells. Next, the relationship between the cytopathic activity of OBP-301, CAR expression, and telomerase activity in human sarcoma cells was assessed. The in vivo antitumor effect of OBP-301 was also confirmed using orthotopic animal models. Finally, the anti-tumor effect of OBP-405 against OBP-301-resistant sarcoma cells was evaluated in vitro and in vivo.