Overcoming the blood-brain barrier with nanoparticle vaccines against gliomas

项目摘要 虽然活化的T细胞穿过血脑屏障（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，释放免疫疗法 对抗GBM需要激活肿瘤微环境（TME）的新技术， 接合先天和适应性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）制剂， 图4显示了针对个性化肿瘤衍生mRNA的异质群组的应答。通过将肿瘤mRNA分层到 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荷（每 粒子）触发有效的先天激活，然后促进适应性效应器反应。我们的技术 在免疫原性差的小动物和自发性大动物胶质瘤模型中释放活性。 RNA-NPs激活系统性/肿瘤内树突状细胞（DC），上调肿瘤细胞中的关键先天基因特征， 胶质瘤TME，并诱导胶质瘤特异性T细胞免疫。在对免疫检查点耐药的小鼠肿瘤模型中 抑制剂，RNA-NP诱导具有长期存活益处的稳健的抗肿瘤功效。我们先前已经 在急性/慢性小鼠GLP毒性研究中证明了RNA-NP的安全性，并启动了大型动物试验。 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， 安全和免疫活性，改善患有终末胶质瘤的宠物犬的总生存率（与 历史对照）。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。 在这个建议中，我们将探讨先天调节和适应性反应的机制基础 在RNA-NP之后。我们的实验将在临床相关的小型和大型动物胶质瘤中进行 模型，其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-NPs重新编程胶质瘤微环境，从而在神经细胞中解锁疫苗应答， BBB.我们的具体目标是： 1.建立RNA-NPs作为胶质瘤免疫原性的先天生物调节剂。 2.阐明肿瘤后天然和适应性抗胶质瘤免疫之间的相互作用机制 特异性RNA-NPs。 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。

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.