Development of oncolytic virotherapy against the refractory gynecologic cancers

在过去的几十年里，尽管难治性妇科肿瘤的化疗取得了巨大的发展，但晚期病例的预后仍然令人不满意，迫切需要新的治疗方式。我们开发了使用端粒酶特异性复制选择性腺病毒（OBP-301）治疗实体瘤的病毒疗法，其中插入了人类端粒酶逆转录酶（hTERT）基因启动子来指导肿瘤特异性E1基因的表达。用OBP-301体外处理卵巢癌细胞可诱导显著的细胞死亡，呈剂量依赖性，而正常细胞无明显死亡。异种移植小鼠卵巢癌细胞模型显示，端粒溶酶能提高小鼠的存活率。这些发现支持了溶瘤病毒的治疗潜力。GFP基因由cmv启动子驱动的OBP401仅在端粒酶阳性细胞中选择性复制，因此可能是癌症筛查的工具。我们从宫颈癌患者的血液样本中收集了一个带有GFP的单细胞，并在CTC和原始癌组织中检测到相同的hpv基因型。提示通过OBP401检测CTC是一种有用的无创诊断方法，可用于肿瘤筛查和早期发现复发性恶性肿瘤。

Despite tremendous development in chemotherapy for refractory gynecologic cancers over the past few decades, the prognosis of the advanced cases is still unsatisfactory, and novel treatment modalities are urgent needed. We developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses(OBP-301), in which the human telomerase reverse transcriptase(hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In vitro treatment of Ovarian cancer cell with OBP-301 induced significant cell death in dose-dependent manner, although normal cells showed no significant cell death. Xenograft mouse model of ovarian cancer cells showed the improved survival of mice treated with Telomelysin. These findings support the therapeutic potential of virotherapy using oncolytic virus.OBP401 in which GFP gene is driven by the CMV-promotor, selectively replicates only in telomerase-positive cells, and therefore may be a tool for cancer screening. We collected a single cell with GFP from blood samples of cervical cancer patients and detected the same HPV-genotype in both CTC and original cancer tissues. This finding suggests that CTC detecting by OBP401 is the useful non-invasive diagnostic way for cancer screening and early detection of recurrent malignant tumors.