Harnessing the Immunologic Capacity of RNA-nanoparticle Vaccines Targeting Glioblastoma

利用针对胶质母细胞瘤的 RNA 纳米颗粒疫苗的免疫能力

基本信息

批准号：
9352288
负责人：
Elias Sayour
金额：
$ 15.82万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-13 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352288
关键词：
Advisory Committees Affect Antigen-Presenting Cells Antigens Area Autologous Dendritic Cells Biopsy Blinded Bypass Cancer Biology Cations Cells Cessation of life Clinical Collection Dendritic Cell Vaccine Dendritic Cells Development Development Plans Developmental Therapeutics Program Disease Progression Drug Delivery Systems Encapsulated Engineering Ensure Excision Faculty Fellowship Florida Formulation Freund&apos s Adjuvant Generations Glioblastoma Glioma Global Change Growth Hepatic Hour Human Immune Immune response Immune system Immunity Immunologics Immunotherapeutic agent Immunotherapy Intracranial Neoplasms Intravenous Knowledge Lipids Liposomes Liver Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Marketing Mediating Medicine Mentors Messenger RNA Modality Modeling Molecular Biology Monoclonal Antibodies Mus Nanotechnology Nature Nucleic Acids Operative Surgical Procedures Organ PDCD1LG1 gene Pathway interactions Patient-Focused Outcomes Patients Pediatrics Peptide Vaccines Peripheral Phenotype Physiologic pulse Physiological Positioning Attribute Preparation Production RNA Randomized Refractory Regulatory Pathway Research Design Research Personnel Role Route Safety Small Interfering RNA Solid Neoplasm Spleen T cell response T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Time Toxic effect Transfection Translations Treatment outcome Tumor Immunity Tumor-Derived United States National Institutes of Health Universities Up-Regulation Vaccination Vaccines cancer immunotherapy career development chemoradiation clinical application clinically translatable combinatorial commercialization cost cytokine effective therapy experience immune activation immunoregulation improved innovation nanoliposome nanoparticle neoplastic cell neurosurgery new therapeutic target novel novel therapeutics oncology pre-clinical professor targeted treatment therapeutic RNA tumor tumor immunology uptake vaccine development

项目摘要

Abstract: I am now in my first faculty position as an Assistant Professor of Neurosurgery and Pediatrics at the University of Florida. I completed a T32 NIH fellowship at Duke University in Cancer Biology and Developmental Therapeutics before accepting a junior faculty position at the University of Florida where I moved with my mentor, Dr. Duane Mitchell. Dr. Mitchell and I have selected an advisory committee to ensure accrual of my intellectual and professional growth. The non-overlapping expertise of our advisory committee will be an avenue for me to develop new knowledge in tumor immunology, molecular biology, nanotechnology and translational oncology. This proposal will leverage much of this experience as it outlines a career development plan for me to become an independent investigator exploring novel RNA-nanoparticle vaccines that can re- direct the immune system against malignant brain tumors. Background: Glioblastoma (GBM) remains almost uniformly lethal with a median survival of less than 15 months thus necessitating the development of more efficacious and targeted therapeutics. While we have shown in a randomized/blinded trial that RNA-pulsed dendritic cell (DC) vaccines elicit significant survival benefits in GBM patients, these therapies remain encumbered by cost and complexity. Alternatively, RNA- nanoparticles (RNA-NPs) can deliver total tumor RNA (TTRNA), extracted and amplified from as few as 500 biopsied tumor cells, to endogenous antigen presenting cells (APCs) inducing potent, nontoxic anti-tumor immunity. Since these nanoliposomes have been used with limited toxicity in clinical-grade medicine, are stable for several hours in solution, protect nucleic acids from degradation, and can be engineered to modulate immune responses, we have explored the use of TTRNA-loaded NPs as an attractive, “off-the-shelf” therapeutic platform to re-direct host-immunity against intracranial tumors. While we have demonstrated that intravenous delivery of RNA-NPs mediate antigen specific T cell responses against intracranial malignancies comparable to DC vaccines, these formulations were shown to induce differential phenotypes on APCs in the spleen and liver. Hypothesis: RNA-NPs transfect distinct APCs in the spleen and liver inducing differential immune responses that can be modulated in favor of enhanced effector functions. Specific Aims: 1) Determine critical APC subsets and evaluate their role in RNA-NP mediated immune responses. 2) Identify regulatory pathways involved in RNA-NP mediated immunity and investigate capacity to target these pathways through incorporation of immunomodulatory RNAs into vaccine formulations. 3) Evaluate the safety and efficacy of the most promising RNA-NP formulation in a malignant murine glioma model. Research Design: We propose to identify critical APCs involved in RNA-NP mediated immunity, target regulatory pathways identified after vaccination, and evaluate the safety and efficacy of RNA-NPs in an invasive preclinical murine malignant glioma model. Since this platform can deliver combinatorial therapies using a single delivery platform, we will investigate if RNA-NP co-delivery of RNAs (i.e. small interfering RNAs or RNAs encoding for monoclonal antibodies) targeting regulatory pathways (i.e. programmed death-ligand 1) can potentiate our vaccine’s already promising anti-tumor immunity. Innovation: Since RNA-NPs bypass the complexity of cellular therapeutics, are amenable to central distribution, and can be made within days of tumor resection, these formulations supplant DC vaccines providing near immediate immune induction against inciting malignancies. By employing liposomal RNA-NPs encoding for both tumor RNAs and immunomodulatory molecules, as an innovative and versatile platform for delivering combinatorial therapeutics via a single treatment modality, we can rapidly screen strategies to enhance the efficacy of our vaccine platform. Potential Impact: Despite aggressive and highly toxic multi-modal therapy, GBM remains invariably recalcitrant. RNA-NP vaccines can provide a more effective and specific therapy critical in improving clinical outcomes for patients affected by GBMs without adding further toxicity to existing treatments. This novel therapeutic platform has potential to better understand the immunologic potential of RNA-NPs and contains a wide range of clinical application for all malignancies that can be targeting using TTRNA obtained from surgical resection of solid tumors.

抽象的：我现在的第一个教职是大学神经外科和儿科助理教授我在杜克大学完成了 T32 NIH 癌症生物学和发育研究奖学金在接受佛罗里达大学初级教职之前的治疗学，我和我的同事搬到了那里导师杜安·米切尔博士和我选择了一个咨询委员会来确保我的收益的累积。我们的咨询委员会的不重叠的专业知识将是一个知识和专业发展。为我发展肿瘤免疫学、分子生物学、纳米技术和该提案将利用大部分经验来概述职业发展。计划让我成为一名独立研究者，探索新型 RNA 纳米颗粒疫苗，这些疫苗可以重新指导免疫系统对抗恶性脑肿瘤。背景：胶质母细胞瘤 (GBM) 几乎都是致命的，中位生存期低于 15 因此，我们需要开发更有效、更有针对性的治疗方法。随机/盲法试验表明，RNA 脉冲树突状细胞 (DC) 疫苗可显着提高存活率这些疗法虽然对 GBM 患者有好处，但仍然受到成本和复杂性的阻碍。纳米颗粒 (RNA-NP) 可以提供总肿瘤 RNA (TTRNA)，从少至 500 个细胞中提取并扩增活检肿瘤细胞，转化为内源性抗原呈递细胞 (APC)，诱导有效、无毒的抗肿瘤作用由于这些纳米脂质体已在临床级药物中使用，毒性有限，因此在溶液中稳定数小时，保护核酸免遭降解，并且可以进行工程改造以调节免疫反应，我们探索了使用装载 TTRNA 的 NP 作为一种有吸引力的“现成” 虽然我们已经证明了这一点，但我们已经证明了这一点。静脉注射 RNA-NP 介导针对颅内恶性肿瘤的抗原特异性 T 细胞反应与 DC 疫苗相比，这些制剂被证明可以在 APC 上诱导差异表型脾脏和肝脏。假设：RNA-NPs 转染脾脏和肝脏中不同的 APC，诱导不同的免疫反应可以对其进行调节以有利于增强效应器功能。具体目标： 1) 确定关键的 APC 子集并评估它们在 RNA-NP 介导的免疫反应中的作用。 2) 确定参与 RNA-NP 介导免疫的调节途径并研究靶向能力通过将免疫调节 RNA 掺入疫苗制剂中来实现这些途径。 3) 评估最有前途的 RNA-NP 制剂在恶性小鼠神经胶质瘤中的安全性和有效性模型。研究设计：我们建议鉴定参与 RNA-NP 介导的免疫的关键 APC，目标疫苗接种后确定的调控途径，并评估 RNA-NP 在疫苗接种中的安全性和有效性侵入性临床前小鼠恶性胶质瘤模型，因为该平台可以提供组合疗法。使用单一递送平台，我们将研究 RNA-NP 共同递送 RNA（即小干扰 RNA）是否或编码单克隆抗体的RNA）靶向调节途径（即程序性死亡配体1）可以增强我们疫苗已经很有希望的抗肿瘤免疫力。创新：由于 RNA-NP 绕过了细胞治疗的复杂性，因此适合中央治疗这些制剂可以在肿瘤切除后几天内进行分配，并取代 DC 疫苗通过使用脂质体 RNA-NP，提供针对诱发恶性肿瘤的近乎即时的免疫诱导。编码肿瘤 RNA 和免疫调节分子，作为创新和多功能平台通过单一治疗方式提供组合疗法，我们可以快速筛选策略增强我们疫苗平台的功效。潜在影响：尽管采取了积极且高毒性的多模式治疗，GBM 仍然顽固不化。 RNA-NP 疫苗可以提供更有效、更特异的治疗方法，对于改善临床结果至关重要这种新颖的治疗平台不会增加现有治疗的进一步毒性。有潜力更好地了解 RNA-NP 的免疫学潜力，并包含广泛的临床研究适用于所有可以使用从实体瘤手术切除获得的 TTRNA 进行靶向治疗的恶性肿瘤肿瘤。