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 胶质母细胞瘤仍然对治疗，复发几乎是普遍的。特别是针对性的 鉴于这些疗法的表达或存在分子靶标的异质性，疗法失败 跨肿瘤。溶瘤病毒疗法（OV）是一种抗肿瘤策略，在其中病毒选择性复制和 杀死大脑中的肿瘤细胞，并可能激活抗肿瘤的免疫反应。最初的研究表明 OV效率的瓶颈是病毒在人脑中的分布差。克服这一点 挑战，在上一个孢子资金期间，我们调查了交付的可行性和安全性 使用神经干细胞（NSC）的恶性神经胶质瘤患者的肿瘤腺病毒对肿瘤性肿瘤大脑（NSC） 可以携带OV，并迁移到渗透大脑的远处肿瘤口袋。我们进行了1期试验 在其中我们显示了可行性，安全性并确定了该疗法的最大耐受剂量 （NCT03072134）并发表了柳叶刀肿瘤学的结果。该程序的下一步是执行 第二阶段试验以使用总生存率作为效率的终点来研究OV的效率。但是， 第二阶段的试验需要通过提出的其他研究在此延续1的资金中进行优化1） 随着时间的流逝，可以通过新型的脑部实质基质导管来完成多次注射 交付系统（Renishaw®）。 2）使用N-乙酰囊体酰胺最大化NSC生存能力和OV产生 （NACA），我们展示的旨在提高本疗法的递送和效率，以及3） 易于OV的肿瘤患者。我们假设只有一部分患者可能有 容易受到OV的肿瘤，并且鉴定易感肿瘤将允许阐明 效率信号。在此继续续签项目1中，我们现在提出以下具体目标： 特定目的1：使用新型导管方法进行多个导管方法进行1B阶段扩展试验 在新诊断的恶性神经胶质瘤中注射产品 具体目的2：检查预先存在的肿瘤微环境，NACA对病毒复制的影响和 恶性神经胶质瘤患者NSC-OV治疗期间的免疫反应。 特定目标3：使用成对的胶质瘤对溶瘤病毒的敏感性验证基因 分析预处理和治疗期间人神经胶质瘤标本