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

针对新诊断胶质母细胞瘤的 RNA 脂质颗粒疫苗的 I 期研究，IND19304 08/21/2020

基本信息

批准号：
10281384
负责人：
Elias Sayour
金额：
$ 126.25万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10281384
关键词：
phase study RNA lipid particle

项目摘要

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.

项目摘要：尽管有最大手术切除，外束放射疗法和化学疗法，诊断后的18个月以上的胶质母细胞瘤（GBM）患者；这些结果需要开发新的目标疗法。为了解决这一差距，我们的小组开发了一种新型疫苗可以在数小时内解锁抗肿瘤免疫学的形成。通过将肿瘤mRNA分层纳米脂质配方（用于全身给药），我们可以使肿瘤抗原像全身病毒一样出现感染。我们的多层设计可提供抗原负荷增加（每个粒子），触发了有效的先天性激活，然后促进适应性效应子的反应。 RNA-脂质纳米颗粒（RNA-LPS）激活全身/肿瘤内树突状细胞（DC）上调神经胶质瘤的关键先天基因特征微环境，并诱导胶质瘤特异性T细胞免疫史。在耐免疫的鼠肿瘤模型中检查点抑制剂，RNA-LP诱导稳健的抗肿瘤效率，并具有长期幸存者益处。我们有以前证明了RNA-LPS在急性/慢性鼠GLP毒性研究中的安全性，并发起了大型动物犬神经胶质瘤试验（IACUC＃201609430）。我们的犬类试验表明，RNA-LP给药是可行，安全且免疫学上的活动，并在终末神经胶质瘤的宠物犬中提高了总体存活率（与历史对照相比）。此后，我们已获得FDA-Ind批准（BB-Ind＃19304，Sayour）对GBM患者的人类内研究（NCT04573140）。这项研究的目的是评估安全性，新诊断的成年GBM中RNA-LPS疫苗的最大耐受剂量（MTD）和免疫原性患者。我们假设RNA-LP将介导GBM解锁的全身免疫重编程免疫治疗活性。我们的具体目的是： 1。进行I期研究评估RNA-LPS针对GBM的安全性，MTD和免疫原性的行为。一个。在接受RNA-LPS之前表征患者的全身免疫反应，并作用疫苗接种后改变。我。识别髓样和淋巴细胞亚群的免疫学表型（幼稚，效应子，记忆，诊断和整个治疗中GBM患者的调节）和NK细胞。 ii。阐明细胞因子谱和病原体识别受体（PRR）激活的变化 RNA-LP疫苗期间/之后GBM患者的状态。 iii。通过整个外显子识别潜在的肿瘤特异性抗原作为疫苗的候选测序，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。确定抗肿瘤先天和适应性免疫的大小和持久性是否存在与临床结果。