Neuroendocrine neoplasms represent a heterogenous group of rare tumors whose current therapeutic options show only limited efficacy. Oncolytic viruses exert their mode of action through (onco-)lysis of infected tumor cells and the induction of a systemic antitumoral immune response in a virus-induced inflammatory micromilieu. Here, we investigated the potential of our well-established second-generation suicide-gene armed oncolytic measles vaccine virus (MeV-SCD) in five human NEN cell lines. First, (i) expression of the MeV receptor CD46 and (ii) its correlation with primary infection rates were analyzed. Next, (iii) promising combination partners for MeV-SCD were tested by employing either the prodrug 5-fluorocytosine, which is converted into the chemotherapeutic compound 5-fluorouracil, or the mTOR-inhibitor everolimus. As a result, MeV-SCD was found to kill all NEN tumor cell lines efficiently in a dose-dependent manner. This oncolytic effect was further enhanced by exploiting the prodrug-converting system, which was found to be highly instrumental in overcoming the partial resistance found in a single NEN cell line. Furthermore, viral replication was unaffected by everolimus, which is a basic requirement for combined use in NEN patients. These data suggest that MeV-SCD has profound potential for patients with NEN, thus paving the way for early clinical trials.
神经内分泌肿瘤是一组异质性罕见肿瘤，当前治疗方案疗效有限。溶瘤病毒通过感染肿瘤细胞的（溶瘤性）裂解作用，在病毒诱导的炎症微环境中引发系统性抗肿瘤免疫反应。本研究在五种人类神经内分泌肿瘤细胞系中，评估了我们已建立的第二代自杀基因武装型溶瘤麻疹疫苗病毒（MeV-SCD）的治疗潜力。首先分析：（i）麻疹病毒受体CD46的表达情况；（ii）该表达与初始感染率的相关性。随后（iii）通过联用前体药物5-氟胞苷（可转化为化疗化合物5-氟尿嘧啶）或mTOR抑制剂依维莫司，测试与MeV-SCD具有协同作用的联合治疗方案。结果显示：MeV-SCD能以剂量依赖性方式有效杀伤所有神经内分泌肿瘤细胞系。前体药物转化系统的应用进一步增强了这种溶瘤效应，该体系对克服单个神经内分泌肿瘤细胞系表现出的部分耐药性具有重要作用。此外，依维莫司不影响病毒复制，这为神经内分泌肿瘤患者的联合用药提供了基本前提。这些数据表明MeV-SCD对神经内分泌肿瘤患者具有显著治疗潜力，为开展早期临床试验奠定了基础。
In Vitro Sensitivity of Neuroendocrine Neoplasms to an Armed Oncolytic Measles Vaccine Virus
肿瘤(癌症)患者之家