Engineering RNA-nanoparticles to enhance dendritic cell mediated treatment of glioblastoma

工程RNA纳米颗粒增强树突状细胞介导的胶质母细胞瘤治疗

• 批准号: 9918273
• 负责人: Adam Grippin
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-16 至 2021-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918273
• 关键词: Achievement; Adoption; Adult; Aftercare; Antitumor Response; Biocompatible Materials; Biological Assay; Brain Neoplasms; Cancer Etiology; Cations; Cells; Clinical; Clinical Research; Clinical Trials; Clinical trial protocol document; Collaborations; Data; Dendritic Cell Vaccine; Dendritic Cells; Dendritic cell activation; Detection; Development; DsRed; Engineering; Europe; Excision; Failure; Formulation; Future; Genomics; Glioblastoma; Glioma; Goals; Hour; Human; Image; Immune; Immunotherapy; In Vitro; Label; Laboratories; Magnetic Resonance Imaging; Magnetism; Malignant neoplasm of brain; Measurement; Measures; Mediating; Medical; Methods; Modeling; Modification; Morbidity - disease rate; Multi-Institutional Clinical Trial; Mus; Nature; Operative Surgical Procedures; Outcome Measure; Patients; Predictive Value; Progression-Free Survivals; Protocols documentation; RNA; RNA delivery; Radiation therapy; Radio; Randomized; Reporting; Research Personnel; Resistance; Signal Pathway; Surrogate Endpoint; T cell response; T-Cell Activation; T-Lymphocyte; TLR7 gene; Techniques; Testing; Translations; Vaccinated; Vaccination; Vaccines; anti-tumor immune response; antigen-specific T cells; base; cell killing; cell motility; cell preparation; chemotherapy; childhood cancer mortality; control trial; conventional therapy; cost; cytotoxicity; design; imaging capabilities; imaging modality; improved; intradermal injection; iron oxide; iron oxide nanoparticle; lymph nodes; migration; mortality; mouse model; nanoparticle; neoplasm immunotherapy; new therapeutic target; particle; patient response; patient subsets; programs; radioresistant; single photon emission computed tomography; superparamagnetism; temozolomide; theranostics; therapeutic vaccine; tool; treatment response; tumor; vaccine efficacy

Abstract Despite aggressive chemotherapy, surgical resection, and radiation therapy, glioblastoma (GBM) remains almost universally fatal. A recent randomized, control trial demonstrated RNA-loaded dendritic cell (DC) vaccines significantly prolong overall and progression free survival in patients with primary GBM. Moreover, this trial also demonstrated that dendritic cell migration to lymph nodes could be used a clinically meaningful predictor of patient response to treatment. This technique provides researchers a surrogate endpoint to develop enhanced dendritic cell vaccine protocols and could provide clinicians with a powerful tool to predict patient response to treatment just 48 hours after vaccination. However, the high regulatory requirements associated with standard methods of tracking cell migration limit future application of this technique. This project is designed to evaluate use of theranostic RNA-loaded nanoparticles (RNA-NPs) to enhance and track DC migration to LNs. Preliminary evidence indicates that RNA-NPs 1) stimulate potent DC activation 2) enhance DC migration to LNs, and 3) can be loaded with sufficient levels of iron oxide to be tracked with MRI. This study will test the hypothesis that RNA-NPs can be used to enhance DC migration to LNs, predict vaccine efficacy with MRI, and improve antitumor immune responses. These goals will be assessed with the following Specific Aims: Aim 1: Determine effects of RNA-NP loading on dendritic cell activation and migration to LNs Unique benefits of RNA-NP loading on DC activation will be assessed with genomic analysis of intracellular signaling pathways. Functional consequences of RNA-NP loading will be determined in a murine model of our vaccine protocol. Aim 2: Determine predictive utility of MRI-detected dendritic cell migration The sensitivity of MRI based detection of RNA-NP loaded DCs will be determined by correlating changes in MRI intensity to absolute counts of RNA-NP-loaded DsRed+ DCs in lymph nodes. The predictive value of MRI- detected DC migration will then be assessed in a murine glioma model. Aim 3: Evaluate efficacy of RNA-NP loaded dendritic cells in a murine model of GBM Mice will be vaccinated with RNA-NP-loaded DCs. Antigen specific T cell activation will be assessed with a T cell killing assay. Survival benefit over other DC preparation methods will be assessed in an aggressive temozolomide and radiation resistant murine model of high grade glioma. Significance This project promises to produce a powerful tool to enhance and predict long term survival in patients with GBM. The combination of a readily accessible imaging component with a robustly stimulatory nanoparticle formulation would allow streamlined manufacturing of a low cost, theranostic nanoparticle that would provide clinicians an unprecedented advantage in patient management.

摘要 尽管有积极的化疗，手术切除和放射治疗，胶质母细胞瘤（GBM）仍然存在。 几乎是致命的最近的一项随机对照试验表明，RNA负载的树突状细胞（DC） 疫苗显著延长了原发性GBM患者的总体和无进展生存期。此外，委员会认为， 该试验还表明，树突状细胞向淋巴结的迁移可用于临床上有意义的研究。 预测患者对治疗的反应。这项技术为研究人员提供了一个替代终点， 开发增强的树突状细胞疫苗方案，可以为临床医生提供一个强大的工具来预测 患者在接种疫苗后48小时内对治疗产生反应。然而，高监管要求 与跟踪细胞迁移的标准方法相关的技术限制了该技术的未来应用。 该项目旨在评估使用治疗诊断RNA负载纳米颗粒（RNA-NPs）来增强和 跟踪DC迁移到LN。初步证据表明RNA-NPs 1）刺激有效的DC活化2） 增强DC向LN的迁移，和3）可以负载足够水平的氧化铁以用MRI追踪。 本研究将验证RNA-NPs可用于增强DC向淋巴结迁移的假设，预测疫苗 MRI疗效，并改善抗肿瘤免疫应答。这些目标将通过以下方面进行评估 具体目标： 目的1：确定RNA-NP负载对树突状细胞活化和向LN迁移的影响 RNA-NP负载对DC活化的独特益处将通过细胞内的基因组分析来评估。 信号通路RNA-NP加载的功能结果将在我们的小鼠模型中确定。 疫苗方案。 目的2：确定MRI检测的树突状细胞迁移的预测效用 基于MRI的检测加载RNA-NP的DC的灵敏度将通过将MRI中的变化相关联来确定。 淋巴结中负载RNA-NP的DsRed+ DC的绝对计数的强度。MRI的预测价值- 然后在鼠神经胶质瘤模型中评估检测到的DC迁移。 目的3：评价RNA-NP负载的树突状细胞在GBM的鼠模型中的功效 小鼠将用加载RNA-NP的DC接种。抗原特异性T细胞活化将用T细胞活化试验评估。 细胞杀伤测定。与其他DC制备方法相比的生存益处将在一项积极的研究中评估。 替莫唑胺和放射抗性高级别胶质瘤小鼠模型。 意义该项目有望产生一个强大的工具，以提高和预测长期生存， GBM患者容易接近的成像组件与稳健的刺激性成像组件的组合， 纳米颗粒制剂将允许低成本的治疗诊断纳米颗粒的流线型制造， 将为临床医生提供前所未有的病人管理优势。