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.

项目摘要虽然激活的T细胞越过血脑屏障（BBB），但免疫疗法尚未针对靶向由于GBM的异质性和免疫抑制微环境而引起的治疗。释放免疫疗法反对GBM需要激活肿瘤微环境（TME）的新技术，而同时也让先天和适应性臂互动以产生持续的细胞免疫力。我们开发了一种新型的RNA纳米颗粒（RNA-NP），该粒子可以同时编排先天/自适应反应反应异质的个性化肿瘤衍生的mRNA。通过将肿瘤mRNA分层多层纳米脂质配方（用于全身给药），我们可以提供增加的抗原载荷（PER 粒子）触发潜在的先天激活，然后促进自适应效应子响应。我们的技术在不良的免疫原性小动物和赞助大型动物神经胶质瘤模型中释放活性。 RNA-NP激活全身/肿瘤内树突状细胞（DC），上调关键的先天基因特征神经胶质瘤TME，并诱导胶质瘤特异性T细胞免疫史。在耐免疫检查点具有耐鼠肿瘤模型抑制剂，RNA-NP诱导稳健的抗肿瘤效率，并具有长期生存益处。我们以前有在急性/慢性鼠GLP毒性研究中证明了RNA-NP的安全性，并引发了大型动物犬神经瘤试验（IACUC＃201609430）。我们的犬类试验表明，RNA-NP给药是可行的，安全且免疫学上的活跃，在终末神经胶质瘤的宠物犬的总生存率上有所改善（比较具有历史控制）。此后，我们获得了FDA-Ind批准（BB-Ind＃19304，Sayour）对GBM患者的研究。在此提案中，我们将探讨用于先天调制和适应性响应的机械基础遵循RNA-NP。我们的实验将在临床相关的大小动物神经胶质瘤中进行模型，这些模型在转化为人类临床试验之前概括了许多人类GBM特征。我们假设RNA-NP重新编程了胶质瘤微环境解锁疫苗反应 BBB。我们的具体目标是： 1。建立RNA-NP作为胶质瘤免疫原性的先天生物调节剂。 2。肿瘤后的先天性和适应性抗脱光瘤免疫学之间的机械相互作用特定的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患者的NP。