Neural Stem Cell Based Virotherapy for Malignant Glioma

基于神经干细胞的恶性胶质瘤病毒疗法

• 批准号: 10626393
• 负责人: MACIEJ S LESNIAK
• 金额: $ 27.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626393
• 关键词: Address; Amides; Biological Markers; Biological Models; Biopsy; Brain; CRISPR screen; Candidate Disease Gene; Carrier Proteins; Catheters; Cell Nucleus; Cell Survival; Cells; Clinical Protocols; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Distant; Drug Delivery Systems; Excision; Funding; Future; Gene Expression; Genes; Glioblastoma; Glioma; Heterogeneity; Human; Immune response; Immunofluorescence Immunologic; Implant; In Vitro; Industry; Infection; Infiltration; Injection product; Injections; Investigation; Knock-out; Macrophage; Malignant Glioma; Malignant neoplasm of brain; Maximum Tolerated Dose; Methods; N-Acetylcysteinamide; Neoadjuvant Therapy; Newly Diagnosed; Oncology; Oncolytic viruses; Outpatients; Overlapping Genes; Patient Selection; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Predisposition; Production; Publishing; Recurrence; Safety; Sampling; Signal Transduction; Specimen; Susceptibility Gene; System; Testing; Time; Tissues; Treatment Efficacy; Tumor Tissue; Viral; Virotherapy; Virus; Virus Replication; anti-tumor immune response; conditionally replicative adenovirus; design; in vivo Model; interest; migration; molecular targeted therapies; neoplastic cell; nerve stem cell; novel; nucleocytoplasmic transport; oncolytic adenovirus; oncolytic virotherapy; particle; patient biomarkers; patient stratification; patient subsets; phase I trial; phase II trial; predictive marker; programs; resilience; safety and feasibility; single-cell RNA sequencing; stem cells; targeted treatment; therapeutic effectiveness; therapeutic evaluation; transcriptomics; translational approach; treatment optimization; tumor; tumor microenvironment

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

项目 1：项目摘要 胶质母细胞瘤对治疗仍然有抵抗力，并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标的表达或存在的异质性，疗法会失败 跨越肿瘤。溶瘤病毒疗法 (OV) 是一种抗肿瘤策略，其中病毒选择性复制和 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 功效的一个瓶颈是病毒在人脑中的分布不良。为了克服这个 挑战，在上一次 SPORE 资助期间，我们调查了交付的可行性和安全性 使用神经干细胞 (NSC) 将溶瘤腺病毒注入恶性胶质瘤患者的肿瘤周围大脑 它可以携带 OV，并迁移到远处的肿瘤袋，浸润大脑。我们进行了第一阶段试验 我们展示了该疗法的可行性、安全性并确定了最大耐受剂量 （NCT03072134）并将结果发表在《柳叶刀肿瘤学》上。该程序的下一步是执行 II 期试验以总生存期作为疗效终点来研究 OV 的疗效。然而，一个 II 期试验需要通过本次持续资助中提出的额外研究来优化 1) 通过一种新型的基于脑实质导管的方法可以随着时间的推移进行多次注射 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 OV 产量 （NACA），我们证明它可以增强这种疗法的实施和功效，以及 3）先验识别 患有对 OV 敏感的肿瘤的患者。我们假设只有一小部分患者可能患有 OV 敏感的肿瘤，并且识别易感肿瘤将有助于阐明 功效信号。在项目 1 的持续更新中，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，以输送多种药物 在新诊断的恶性神经胶质瘤中注射产品 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，以及 恶性胶质瘤患者 NSC-OV 治疗期间的免疫反应。 具体目标 3：使用配对验证与神经胶质瘤对溶瘤病毒易感性有关的基因 治疗前和治疗期间人类神经胶质瘤标本的分析