A phase I study of RNA-lipid particle vaccines for newly-diagnosed glioblastoma, IND19304 08/21/2020

项目概述：尽管采用最大限度手术切除、外照射放射治疗和 化疗后，胶质母细胞瘤(GBM)患者在确诊后仅存活18个月；这些结果 有必要开发新的靶向疗法。为了解决这一差距，我们团队开发了一种新的疫苗 可以在数小时内解锁抗肿瘤免疫的配方。通过将肿瘤信使核糖核酸层叠成多层 纳米脂质制剂(用于全身给药)，我们可以使肿瘤抗原看起来像全身病毒 感染。我们的多层设计提供了更高的抗原性负荷(每个颗粒)，触发了强大的先天 激活，然后促进适应性效应器反应。RNA-脂质纳米粒(RNA-LP)激活 系统/瘤内树突状细胞(DC)在胶质瘤中上调关键先天基因特征 微环境，并诱导胶质瘤特异性T细胞免疫。在免疫耐药的小鼠肿瘤模型中 检查点抑制剂，RNA-LP可诱导强大的抗肿瘤疗效，并可长期存活。我们有 先前在急性/慢性小鼠GLP毒性研究中证明了RNA-LPs的安全性，并推出了一项大型 动物犬脑胶质瘤试验(IACUC#201609430)。我们的犬类试验表明，RNA-LP给药是 可行性、安全性和免疫活性，可改善晚期胶质瘤宠物犬的总体生存 (与历史控制相比)。自那以后，我们已经获得了FDA-IND的批准(BB-IND#19304，Sayour)。 GBM患者的人体研究(NCT04573140)。这项研究的目的是评估其安全性， 新诊断成人GBM最大耐受量(MTD)和RNA-LPS疫苗的免疫原性 病人。我们假设RNA-LPs将介导GBM解锁的系统免疫重编程 免疫治疗活性。我们的具体目标是： 1.进行第一阶段研究，评价针对GBM的RNA-LPs的安全性、MTD和免疫原性。 A.患者在接受RNA-LPs治疗前的全身免疫反应特征和效果 接种疫苗后的变化。 I.确定髓系和淋巴细胞亚群的免疫表型(幼稚、效应、记忆、 GBM患者在诊断时和整个治疗过程中的调节)和NK细胞。 二、阐明细胞因子谱和病原体识别受体(PRR)激活的变化 银屑病患者在RNA-LP疫苗接种期间/之后的状况。 三、通过全外显子组鉴定潜在的肿瘤特异性抗原作为疫苗候选 测序、rna-seq和新抗原预测分析。 B.在接种疫苗的患者中建立记忆回忆T细胞免疫 C.确定抗肿瘤先天免疫和获得性免疫的大小和持久性是否相关 与临床结果相关。

Project Summary: Despite standard of care with maximal surgical resection, external beam radiotherapy, and chemotherapy, patients with glioblastoma (GBM) live little more than 18 months after diagnosis; these outcomes necessitate development of new targeted therapies. To address this gap, our group developed a novel vaccine formulation that can unlock anti-tumor immunity within hours. By layering tumor mRNA into a multi-lamellar nano-lipid formulation (for systemic administration), we can make tumor antigens appear like a systemic viral infection. Our multi-lamellar design delivers increased antigenic load (per particle) triggering potent innate activation which then facilitates adaptive effector responses. RNA-lipid nanoparticles (RNA-LPs) activate systemic/intratumoral dendritic cells (DCs), upregulate critical innate gene signatures in the glioma microenvironment, and induce glioma-specific T cell immunity. In murine tumor models resistant to immune checkpoint inhibitors, RNA-LPs induce robust anti-tumor efficacy with long-term survivor benefits. We have previously demonstrated safety of RNA-LPs in acute/chronic murine GLP toxicity studies and launched a large animal canine glioma trial (IACUC#201609430). Our canine trial demonstrated that RNA-LP 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 (NCT04573140) in patients with GBM. The purpose of this study is to assess the safety, maximum tolerated dose (MTD), and immunogenicity of RNA-LPs vaccines in newly-diagnosed adult GBM patients. We hypothesize that RNA-LPs will mediate systemic immune reprogramming of GBM unlocking immunotherapeutic activity. Our SPECIFIC AIMS are: 1. Conduct phase I study evaluating safety, MTD and immunogenicity of RNA-LPs against GBM. a. Characterize systemic immune response in patients prior to receiving RNA-LPs and effect change following vaccination. i. Identify immunologic phenotype of myeloid and lymphocyte subsets (naïve, effector, memory, regulatory) and NK cells in patients with GBM at diagnosis and throughout therapy. ii. Elucidate changes in cytokine profile and pathogen-recognition receptor (PRR) activation status in patients with GBM during/after RNA-LP vaccines. iii. Identify potential tumor specific antigens as vaccine candidates through whole exome sequencing, RNA-seq, and neoantigen prediction analysis. b. Establish memory recall T cell immunity in vaccinated patients c. Determine if magnitude and persistence of anti-tumor innate and adaptive immunity correlates with clinical outcome.