Fujiwara Toshiyoshi
Department of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
Ann Gastroenterol Surg. 2019 Jul 5;3(4):396-404. doi: 10.1002/ags3.12270. eCollection 2019 Jul.
Replication-selective tumor-specific viruses represent a novel approach for treating neoplastic diseases. These vectors are designed to induce virus-mediated lysis of tumor cells after selective intracellular virus propagation. For targeting cancer cells, the use of tissue- or cell-specific promoters that are expressed in diverse tumor types but silent in normal cells is required. Human telomerase is highly active in more than 85% of primary cancers, regardless of tissue origin, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (telomelysin, OBP-301) in which the hTERT promoter element drives expression of E1 genes. As only tumor cells that express the telomerase can activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Upon US Food and Drug Administration approval, a phase 1 dose-escalation study of intratumoral injection of telomelysin for various solid tumors has been completed to confirm the safety, tolerability, and feasibility of the agent. Moreover, we found that adenoviral E1B 55-kDa protein in telomelysin inhibits the radiation-induced DNA repair machinery. Thus, tumor cells infected with telomelysin could be rendered sensitive to ionizing radiation. Recently, we assessed the safety and efficacy of intratumoral injection of telomelysin with radiotherapy in esophageal cancer patients not suited for standard treatments. This review highlights some very promising clinical advances in cancer therapeutic technologies using telomerase-specific oncolytic virotherapy.
复制选择性肿瘤特异性病毒代表了一种治疗肿瘤疾病的新方法。这些载体旨在通过细胞内选择性病毒增殖来诱导病毒介导的肿瘤细胞裂解。为了靶向癌细胞，需要使用在多种肿瘤类型中表达但在正常细胞中沉默的组织或细胞特异性启动子。人类端粒酶在超过85%的原发性癌症中高度活跃，无论组织来源如何，其活性与人类端粒酶逆转录酶（hTERT）的表达密切相关。我们构建了一种减毒腺病毒5载体（端粒溶瘤病毒，OBP - 301），其中hTERT启动子元件驱动E1基因的表达。由于只有表达端粒酶的肿瘤细胞才能激活该启动子，hTERT近端启动子允许病毒基因在肿瘤细胞中优先表达，从而导致选择性病毒复制和溶瘤性细胞死亡。在美国食品药品监督管理局批准后，已完成一项针对各种实体瘤瘤内注射端粒溶瘤病毒的1期剂量递增研究，以确认该药物的安全性、耐受性和可行性。此外，我们发现端粒溶瘤病毒中的腺病毒E1B 55 kDa蛋白可抑制辐射诱导的DNA修复机制。因此，感染端粒溶瘤病毒的肿瘤细胞可能对电离辐射敏感。最近，我们评估了在不适合标准治疗的食管癌患者中瘤内注射端粒溶瘤病毒联合放疗的安全性和疗效。本综述重点介绍了使用端粒酶特异性溶瘤病毒疗法在癌症治疗技术方面取得的一些非常有前景的临床进展。
