Efficacy of MV-NIS oncolytic measles virus against relapsed / refractory pediatric ALL and safety in the young and markedly immunocompromised primate

MV-NIS 溶瘤麻疹病毒对复发/难治性儿科 ALL 的功效以及年轻和明显免疫功能低下的灵长类动物的安全性

• 批准号: 408429971
• 负责人: Professor Dr. Christian Beltinger
• 金额: --
• 依托单位: Universitätsklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/408429971?language=en
• 关键词: Efficacy; MV; NIS; oncolytic; measles

Recently, the first oncolytic virus has been approved as a drug and the first complete remission of a disseminated cancer after virotherapy has been described in a patient receiving oncolytic measles virus (OMV). We have published that repeated i.v. injections of a laboratory strain of OMV control a moderate load of chemosensitive pediatric acute B-lineage ALL in mice. In the proposed project we aim to prove the efficacy of clinical-grade OMV, called MV-NIS, against pediatric relapsed / refractory ALL, including T ALL, under clinically relevant conditions, and to assess the safety of MV-NIS in young and markedly immunocompromised non-human primates and mice. Based on preliminary encouraging results we will investigate whether a single i.v. injection of MV-NIS suffices to cure mice with very high, widely disseminated loads of ALL xenografts from children that died of their refractory disease. We will explore whether high expression levels of proviral ADAR1 allow selection of patients whose ALL are likely to respond to MV-NIS. We will investigate toxicity of MV-NIS in novel models of very young and markedly immunocompromised non-human primates and mice. The results in these animal models will be important beyond oncolytic MV, as they also relate to the safety of measles vaccination in immunocompromised children. This project promises to meet the prerequisites for rapid clinical translation of this novel therapeutic approach to relapsed / refractory ALL.

最近，第一种溶瘤病毒已被批准作为药物，并且在接受溶瘤麻疹病毒（OMV）的患者中描述了病毒治疗后播散性癌症的首次完全缓解。我们已经发表了重复的 i.v.注射实验室 OMV 菌株可控制小鼠体内中等负荷的化学敏感性儿童急性 B 系 ALL。在拟议的项目中，我们的目标是证明临床级 OMV（称为 MV-NIS）在临床相关条件下对儿科复发/难治性 ALL（包括 T ALL）的功效，并评估 MV-NIS 在年轻和明显免疫功能低下的非人灵长类动物和小鼠中的安全性。根据初步令人鼓舞的结果，我们将调查单次静脉注射是否可以。注射 MV-NIS 足以治愈来自死于难治性疾病的儿童的 ALL 异种移植物负载非常高且广泛传播的小鼠。我们将探讨前病毒 ADAR1 的高表达水平是否允许选择可能对 MV-NIS 产生反应的 ALL 患者。我们将在非常年轻和明显免疫功能低下的非人类灵长类动物和小鼠的新模型中研究 MV-NIS 的毒性。这些动物模型的结果将比溶瘤 MV 更重要，因为它们还关系到免疫功能低下儿童麻疹疫苗接种的安全性。该项目有望满足这种针对复发/难治性 ALL 的新型治疗方法快速临床转化的先决条件。