Overcoming the blood-brain barrier with nanoparticle vaccines against gliomas

利用针对神经胶质瘤的纳米颗粒疫苗克服血脑屏障

基本信息

批准号：
10333358
负责人：
Elias Sayour
金额：
$ 47.66万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10333358
关键词：
Acute Adjuvant Animal Model Animals Attenuated Biological Biological Response Modifiers Biopsy Blood Blood - brain barrier anatomy CCL2 gene CD8-Positive T-Lymphocytes Canis familiaris Cells Cellular Immunity Chemotherapy and/or radiation Chronic Clinical Clinical Trials Clinical Trials Design Data Dendritic Cells Development Dose Evaluation Excision Formulation Glioblastoma Glioma H3 K27M mutation Heterogeneity Hour Human IACUC IFNAR1 gene Immune Immune checkpoint inhibitor Immune system Immunity Immunocompetent Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Interferon-alpha Interferons Knockout Mice Lipids Long-Term Survivors Luciferases Mediating Memory Messenger RNA Modeling Mus Neoadjuvant Therapy Operative Surgical Procedures Pathway interactions Patients RNA Randomized Recurrence Resistance Safety Serum Signal Transduction T memory cell T-Lymphocyte Technology Toll-like receptors Toxic effect Translations Tumor-Derived Vaccines Viremia adaptive immunity arm cell type clinically relevant cohort cytokine effective therapy experimental study first-in-human genetic signature immunogenic immunogenicity interest intravenous administration knockout animal nano nanoparticle new technology novel novel therapeutics novel vaccines particle pathogen phase 1 designs receptor response survival outcome targeted treatment trafficking trial design tumor tumor microenvironment tumor-immune system interactions vaccine immunotherapy vaccine response

项目摘要

Project Summary While activated T cells cross the blood-brain barrier (BBB), immunotherapy has yet to be harnessed for targeted therapy due to GBM’s heterogeneity and immunosuppressive microenvironment. Unleashing immunotherapy against GBM requires new technologies that activate the tumor microenvironment (TME), while concomitantly engaging both innate and adaptive arms to generate sustained cellular immunity. We developed a novel RNA-nanoparticle (RNA-NP) formulation to simultaneously orchestrate innate/adaptive response against a heterogeneous cohort of personalized tumor derived mRNA. By layering tumor mRNA into a multi-lamellar nano-lipid formulation (for systemic administration), we can deliver increased antigenic load (per particle) triggering potent innate activation which then facilitates adaptive effector responses. Our technology unlocks activity in poorly immunogenic small animal and spontaneous large animal glioma models. RNA-NPs activate systemic/intratumoral dendritic cells (DCs), upregulate critical innate gene signatures in the glioma TME, and induce glioma-specific T cell immunity. In murine tumor models resistant to immune checkpoint inhibitors, RNA-NPs induce robust anti-tumor efficacy with long-term survivor benefits. We have previously demonstrated safety of RNA-NPs in acute/chronic murine GLP toxicity studies, and launched a large animal canine glioma trial (IACUC#201609430). Our canine trial demonstrated that RNA-NP administration is feasible, safe and immunologically active with improvement in overall survival in pet dogs with terminal gliomas (compared with historical controls). We have since received FDA-IND approval (BB-IND#19304, Sayour) for first-in-human studies in GBM patients. In this proposal, we will explore mechanistic underpinnings for innate modulation and adaptive response following RNA-NPs. Our experiments will be conducted in clinically relevant small and large animal glioma models, which recapitulate many human GBM features before translation into a human clinical trial. We hypothesize that RNA-NPs reprogram the glioma microenvironment unlocking vaccine response across the BBB. Our SPECIFIC AIMS will be to: 1. Establish RNA-NPs as innate biomodulators of glioma immunogenicity. 2. Elucidate mechanistic interactions between innate and adaptive anti-glioma immunity following tumor specific RNA-NPs. 3. Determine in a neoadjuvant clinical trial design the modulating effects and immunogenicity of RNA- NPs in recurrent GBM patients.

项目概要虽然激活的 T 细胞可以穿过血脑屏障 (BBB)，但免疫疗法尚未用于靶向治疗由于 GBM 的异质性和免疫抑制微环境而导致的治疗。对抗 GBM 需要激活肿瘤微环境 (TME) 的新技术，同时结合先天性和适应性臂来产生持续的细胞免疫。我们开发了一种新型 RNA 纳米颗粒 (RNA-NP) 配方，可同时协调先天/适应性通过将肿瘤 mRNA 分层，针对个性化肿瘤衍生 mRNA 的异质群体做出反应。多层纳米脂质制剂（用于全身给药），我们可以提供增加的抗原负载（每粒子）触发有效的先天激活，然后促进适应性效应器反应。解锁免疫原性差的小动物和自发性大型动物神经胶质瘤模型的活性。 RNA-NPs 激活全身/瘤内树突状细胞 (DC)，上调细胞中关键的先天基因特征神经胶质瘤 TME，并在对免疫检查点耐药的小鼠肿瘤模型中诱导神经胶质瘤特异性 T 细胞免疫。抑制剂、RNA-NPs 可以诱导强大的抗肿瘤功效，并为长期幸存者带来好处。 RNA-NPs在急性/慢性小鼠GLP毒性研究中的安全性，并启动了大型动物犬神经胶质瘤试验（IACUC#201609430）我们的犬试验证明 RNA-NP 给药是可行的，安全且具有免疫活性，可改善患有终末期神经胶质瘤的宠物狗的总体生存率（与此后，我们获得了 FDA-IND 批准（BB-IND#19304，Sayour），用于首次人体试验。 GBM 患者的研究。在本提案中，我们将探索先天调节和适应性响应的机制基础我们的实验将在临床相关的小型和大型动物神经胶质瘤中进行。模型，在转化为人体临床试验之前概括许多人类 GBM 特征。开发 RNA-NP 重新编程神经胶质瘤微环境，解锁整个系统的疫苗反应 BBB。我们的具体目标是： 1. 建立 RNA-NP 作为神经胶质瘤免疫原性的先天生物调节剂。 2. 阐明肿瘤后先天性和适应性抗神经胶质瘤免疫之间的机制相互作用特异性RNA-NP。 3. 在新辅助临床试验设计中确定 RNA-的调节作用和免疫原性复发性 GBM 患者中的 NP。