Overcoming the blood-brain barrier with nanoparticle vaccines against gliomas

项目摘要 当激活的T细胞穿过血脑屏障(BBB)时，免疫疗法尚未被用于靶向治疗 治疗由于GBM的异质性和免疫抑制的微环境。释放免疫疗法 对抗GBM需要新的技术来激活肿瘤微环境(TME)，同时伴随而来的是 使用先天和适应性手臂以产生持续的细胞免疫。 我们开发了一种新的RNA纳米颗粒(RNA-NP)配方，以同时协调先天/适应性 对个体化肿瘤来源的信使核糖核酸异质性队列的反应。通过将肿瘤信使核糖核酸 一种多层纳米脂质制剂(用于全身给药)，我们可以提供更高的抗原量(PER 粒子)触发强大的先天激活，从而促进适应性效应器反应。我们的技术 解锁免疫原性差的小动物和自发性大动物胶质瘤模型的活性。 RNA-NPs激活系统/瘤内树突状细胞(DC)，上调关键的先天基因信号 胶质瘤TME，并诱导胶质瘤特异性T细胞免疫。在免疫检查点耐药的小鼠肿瘤模型中 抑制物，RNA-NPs诱导强大的抗肿瘤效果，长期存活的好处。我们之前已经 在急性/慢性小鼠GLP毒性研究中证明了RNA-NPs的安全性，并启动了一个大型动物 犬脑胶质瘤试验(IACUC#201609430)。我们的犬试验表明，RNA-NP给药是可行的， 安全性和免疫活性，改善了患有终末期胶质瘤的宠物狗的总存活率(比较 具有历史控制)。自那以后，我们已经获得了FDA-IND的批准(BB-IND#19304，Sayour)，成为人类第一人 对GBM患者的研究。 在这个提案中，我们将探索先天调制和适应性反应的机制基础 在RNA-NPs之后。我们的实验将在临床相关的小动物和大动物胶质瘤中进行。 在转化为人类临床试验之前，这些模型概括了许多人类GBM的特征。我们 假设RNA-NPs重新编程胶质瘤微环境，解锁整个 BBB。我们的具体目标是： 1.建立RNA-NPs作为脑胶质瘤免疫原性的天然生物调节剂。 2.阐明肿瘤后先天免疫和获得性抗胶质瘤免疫之间的机制相互作用 特定的RNA-NPs。 3.在新佐剂临床试验设计中确定RNA的调节作用和免疫原性 复发的GBM患者的NPS。

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.