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：尽管采用最大程度的手术切除、外照射放射治疗和化疗后，胶质母细胞瘤 (GBM) 患者在诊断后仅存活 18 个月多一点；为了解决这一空白，我们的团队开发了一种新型疫苗。通过将肿瘤 mRNA 分层成多层，可以在数小时内释放抗肿瘤免疫力。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我们的多层设计可增加抗原负载（每个颗粒），从而触发有效的先天性感染。激活，然后促进适应性效应子反应。全身/肿瘤内树突状细胞 (DC)，上调神经胶质瘤中的关键先天基因特征微环境，并在免疫抵抗的小鼠肿瘤模型中诱导神经胶质瘤特异性 T 细胞免疫。检查点抑制剂、RNA-LP 可诱导强大的抗肿瘤功效，并为幸存者带来长期益处。先前在急性/慢性小鼠 GLP 毒性研究中证明了 RNA-LP 的安全性，并启动了大规模动物犬神经胶质瘤试验 (IACUC#201609430) 我们的犬试验证明 RNA-LP 给药是有效的。可行、安全且具有免疫活性，可改善患有终末期神经胶质瘤的宠物狗的总体生存率（与历史对照相比）我们已获得 FDA-IND 批准（BB-IND#19304，Sayour）。 GBM 患者的人体研究（NCT04573140）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) 和免疫原性我们认为 RNA-LPs 将介导 GBM 解锁的系统免疫重编程。我们的具体目标是： 1. 进行 I 期研究，评估 RNA-LPs 针对 GBM 的安全性、MTD 和免疫原性。 a. 在接受 RNA-LP 之前表征患者的全身免疫反应和效果接种疫苗后发生变化。 i. 识别骨髓和淋巴细胞亚群的免疫表型（幼稚细胞、效应细胞、记忆细胞、 GBM 患者在诊断时和整个治疗过程中使用调节性细胞和 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.在肺炎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久性是否相关与临床结果。