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

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静脉注射实验室株OMV控制中等负荷的化学敏感性小儿急性B系ALL小鼠。在拟议的项目中，我们旨在证明临床级OMV（称为MV-NIS）在临床相关条件下对儿科复发性/难治性ALL（包括T ALL）的疗效，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。基于初步令人鼓舞的结果，我们将研究单次静脉注射MV-NIS是否足以治愈患有非常高的、广泛传播的ALL异种移植物负荷的小鼠，这些小鼠来自死于难治性疾病的儿童。我们将探讨前病毒ADAR 1的高表达水平是否允许选择可能对MV-NIS有反应的ALL患者。我们将研究MV-NIS在非常年轻和明显免疫功能低下的非人灵长类动物和小鼠的新模型中的毒性。这些动物模型的结果将比溶瘤MV更重要，因为它们还涉及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新的治疗方法快速临床转化为复发性/难治性ALL的先决条件。

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.