Neural Stem Cell Based Virotherapy for Malignant Glioma

项目1：项目总结 胶质母细胞瘤对治疗仍然具有弹性，而且复发几乎是普遍的。特别是，有针对性的 鉴于这些疗法的分子靶点的表达或存在的异质性，这些疗法失败了 横跨肿瘤。溶瘤病毒疗法(OV)是一种抗肿瘤策略，病毒选择性地复制和 杀死大脑中的肿瘤细胞，并潜在地激活抗肿瘤免疫反应。初步研究表明， OV疗效的一个瓶颈是病毒在人脑中的分布不佳。要克服这一点 挑战，在过去的孢子资助期内，我们调查了交付的可行性和安全性 神经干细胞瘤周注射溶瘤腺病毒治疗恶性脑胶质瘤 它可以携带卵巢癌，并迁移到渗透到大脑的远处肿瘤袋中。我们进行了一期试验 我们证明了这种疗法的可行性、安全性，并确定了该疗法的最大耐受量。 (NCT03072134)，并在《柳叶刀肿瘤学》上发表了这一结果。此程序的下一步是执行 第二阶段试验，以总生存期为疗效终点，调查OV的疗效。然而，a 第二阶段试验需要通过在继续提供资金的情况下建议的额外研究来优化1) 能够随着时间的推移进行多次注射，通过基于新型脑实质导管的 输送系统(雷尼绍®)。2)使用N-乙酰半胱氨酸酰胺最大限度地提高NSC活力和卵子产量 (NACA)，我们展示了它可以增强这种疗法的交付和疗效，以及3)先验识别 患有OV易感性肿瘤的患者。我们假设只有一部分患者可能患有 对OV易感的肿瘤，以及对易感肿瘤的识别将有助于阐明 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：利用一种新的导管方法进行1B期扩张试验，将 注射用药物治疗新诊断的恶性胶质瘤 具体目标2：检查先前存在的肿瘤微环境，NACA对病毒复制的影响，以及 恶性胶质瘤患者NSC-OV治疗过程中的免疫反应 特定目标3：使用配对验证与胶质瘤对溶瘤病毒易感性有关的基因 人脑胶质瘤治疗前和治疗中标本的分析

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