Background: Ewing sarcoma (EWS) is a rare cancer of the bone and soft tissue, most prevalent in children and young adults. The treatment of EWS has progressed relatively little in over 30 years. Survival rates for patients, particularly those with metastatic and/or relapsed disease remain poor, highlighting the urgent need for innovative treatment options. Methods: Here, we have explored the therapeutic potential of the oncolytic Maraba virus strain MG1 using various in vitro models of EWS, including established cell lines, doxorubicin-resistant derivatives, spheroid cultures and primary patient-derived Ewing sarcoma cell cultures. We examined the direct oncolytic activity of MG1 and its ability to stimulate the immune-mediated killing of EWS by human healthy donor peripheral blood mononuclear cells. Results: We show that MG1 undergoes productive replication and exerts direct oncolysis of established EWS cell lines, doxorubicin-resistant EWS cell lines and patient-derived Ewing sarcoma cell cultures more recently established from tumours. In contrast, primary mesenchymal stem cells (the likely cell of origin of EWS) were resistant to MG1, with IFN-I being a major determinant of tumour cell selectivity. MG1-treated PBMC produced IFN-I and killed EWS cells in vitro, in a natural killer (NK) cell-dependent manner. Conclusions: The ability of MG1 to kill EWS cells directly and stimulate NK cell cytotoxicity against this tumour suggests that MG1 may provide therapeutic benefit for EWS patients where the efficacy of conventional treatments is currently limited.
背景：尤文肉瘤是一种罕见的骨与软组织恶性肿瘤，好发于儿童及青少年群体。三十余年来，该疾病的治疗进展相对缓慢，尤其对于转移性和/或复发性患者，其生存率仍处于较低水平，这凸显了开发创新治疗方案的迫切需求。方法：本研究利用多种尤文肉瘤体外模型（包括已建立的细胞系、阿霉素耐药衍生株、球体培养模型及原代患者来源的尤文肉瘤细胞培养物），系统评估了溶瘤性马拉巴病毒株MG1的治疗潜力。我们检测了MG1的直接溶瘤活性及其刺激健康供体外周血单个核细胞介导的免疫杀伤效应。结果：研究发现MG1能在已建立的尤文肉瘤细胞系、阿霉素耐药细胞系及新近建立的肿瘤来源原代培养细胞中实现有效复制并发挥直接溶瘤作用。与之形成对比的是，原代间充质干细胞（尤文肉瘤的可能起源细胞）对MG1具有抗性，I型干扰素是决定这种肿瘤细胞选择性的关键因素。经MG1处理的外周血单个核细胞可产生I型干扰素，并以自然杀伤细胞依赖的方式在体外杀伤尤文肉瘤细胞。结论：MG1既能直接杀伤尤文肉瘤细胞，又能增强自然杀伤细胞对该肿瘤的细胞毒性，这表明在传统治疗方案疗效有限的临床背景下，MG1可能为尤文肉瘤患者带来治疗获益。
Oncolytic Maraba Virus MG1 Mediates Direct and Natural Killer Cell-Dependent Lysis of Ewing Sarcoma
肿瘤(癌症)患者之家