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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.

项目总结：尽管采用了最大限度的手术切除、体外放射治疗和化疗后，胶质母细胞瘤（GBM）患者在诊断后的生存时间不超过18个月;这些结果需要开发新的靶向治疗。为了解决这个问题，我们的团队开发了一种新的疫苗，配方可以在几小时内释放抗肿瘤免疫力。通过将肿瘤mRNA分层成多层膜，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性病毒感染我们的多层设计提供了增加的抗原负载（每个颗粒），激活，然后促进适应性效应器反应。RNA-脂质纳米颗粒（RNA-LPs）激活系统性/肿瘤内树突状细胞（DC）上调胶质瘤中关键的先天基因特征微环境，并诱导胶质瘤特异性T细胞免疫。在免疫耐受的小鼠肿瘤模型中，检查点抑制剂，RNA-LP诱导强大的抗肿瘤功效，具有长期存活益处。我们有先前在急性/慢性小鼠GLP毒性研究中证明了RNA-LP的安全性，并启动了一项大型的动物犬胶质瘤试验（IACUC#201609430）。我们的犬试验表明，RNA-LP给药在患有终末期胶质瘤的宠物犬中可行、安全且具有免疫活性，可改善总生存期（与历史对照相比）。自那以后，我们获得了FDA-IND批准（BB-IND#19304，Sayour），用于首次- GBM患者的人体研究（NCT 04573140）。本研究的目的是评估安全性， RNA-LPs疫苗在新诊断成人GBM中的最大耐受剂量（MTD）和免疫原性患者我们假设RNA-LPs将介导GBM解锁的系统性免疫重编程，免疫活性我们的具体目标是： 1.开展I期研究，评估RNA-LP针对GBM的安全性、MTD和免疫原性。 a.在接受RNA-LP之前表征患者的全身免疫应答和效果接种疫苗后的变化 I.确定骨髓和淋巴细胞亚群的免疫表型（幼稚、效应、记忆，在诊断时和整个治疗过程中，GBM患者的NK细胞和调节细胞。二.阐明细胞因子谱和病原体识别受体（PRR）激活的变化 RNA-LP疫苗接种期间/之后GBM患者的状态。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物测序、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适应性免疫的强度和持续性是否与临床结果。