Neural Stem Cell Based Virotherapy for Malignant Glioma

项目1：项目概要 胶质母细胞瘤对治疗仍然有弹性，复发几乎是普遍的。特别是，针对 由于这些疗法的分子靶点的表达或存在的异质性 跨肿瘤溶瘤病毒疗法（OV）是一种抗肿瘤策略，其中病毒选择性地复制， 杀死大脑中的肿瘤细胞，并可能激活抗肿瘤免疫反应。初步研究表明， OV有效性的瓶颈是病毒在人脑中的不良分布。为了克服这个 挑战，在过去的SPORE资助期间，我们调查了交付的可行性和安全性， 应用神经干细胞治疗恶性胶质瘤的实验研究 其可携带OV并迁移至远处肿瘤囊袋浸润脑。我们进行了第一阶段试验 我们证明了这种疗法的可行性、安全性，并确定了最大耐受剂量。 （NCT 03072134），并将结果发表在《柳叶刀肿瘤学》上。这个程序的下一步是执行一个 II期试验，以总生存期作为疗效终点，研究OV的疗效。但 II期试验需要通过本次继续资助中提议的额外研究进行优化， 通过一种新型的基于脑实质导管的方法， 输送系统（Renishaw ®）。2)使用N-乙酰半胱氨酸酰胺最大化NSC活力和OV生产 （NACA），我们表明它可以增强这种疗法的递送和疗效，以及3）优先识别 对OV敏感的肿瘤患者。我们假设只有一部分患者可能有 易受OV影响的肿瘤，以及易感肿瘤的鉴定将允许阐明 功效信号在继续更新项目1的过程中，我们现在提出以下具体目标： 具体目标1：利用新型导管方法进行1B期扩展试验， 在新诊断的恶性胶质瘤中注射产品 具体目标2：检查预先存在的肿瘤微环境，NACA对病毒复制的影响， 恶性胶质瘤患者NSC-OV治疗期间的免疫应答。 特异性目标3：使用配对的方法研究与胶质瘤对溶瘤病毒的易感性有关的p53基因 治疗前和治疗中人脑胶质瘤标本的分析

PROJECT 1: PROJECT SUMMARY Glioblastoma remains resilient to therapy and recurrence is almost universal. In particular, targeted therapies fail given the heterogeneity in the expression or presence of molecular targets for these therapies across tumors. Oncolytic virotherapy (OV) is an anti-tumoral strategy where viruses selectively replicate and kill tumor cells in the brain and potentially, activate anti-tumoral immune response. Initial studies showed that a bottleneck for the efficacy of OV was poor distribution of virus in the human brain. To overcome this challenge, over the last SPORE funding period, we investigated the feasibility and safety of delivering oncolytic adenovirus to the peri-tumoral brain of malignant glioma patients using neural stem cells (NSC) which can carry OV, and migrate to distant tumor pockets infiltrating the brain. We conducted a Phase 1 trial in which we showed the feasibility, safety and established a maximally-tolerated dose for this therapy (NCT03072134) and published the results in Lancet Oncology. The next step in this program is to perform a phase II trial to investigate the efficacy of OV using overall survival as an endpoint for efficacy. However, a phase II trial needs to be optimized via additional studies proposed in this continuation of funding by 1) enabling multiple injections over time, to be accomplished through a novel brain parenchymal catheter-based delivery system (Renishaw ®). 2) maximizing NSC viability and OV production using N-acetylcystein Amide (NACA), which we showed to enhance delivery and efficacy of this therapy, and 3) a priori-identification of patients with tumors that are susceptible to OV. We hypothesize that only a subset of patients might have tumors that are susceptible to OV, and that identification of susceptible tumors will allow elucidation of an efficacy signal. In this continued renewal of Project 1, we now propose the following specific aims: Specific Aim 1: Conduct a phase 1B expansion trial utilizing a novel catheter method to deliver multiple injections of product in newly diagnosed malignant gliomas Specific Aim 2: Examine the pre-existing tumor microenvironment, the effect of NACA on viral replication, and the immune response during NSC-OV therapy in malignant glioma patients. Specific Aim 3: Validate genes that are implicated in glioma susceptibility to oncolytic virus using paired analysis of pre-treatment and during-treatment human glioma specimens