Overcoming metastatic spread of osteosarcoma with RNA loaded nanoparticles

用负载 RNA 的纳米颗粒克服骨肉瘤的转移性扩散

• 批准号: 10522300
• 负责人: Elias Sayour
• 金额: $ 56万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522300
• 关键词: Acute; Adolescent; Adult; Allium cepa; Animals; Antigens; Biological; Biology; Biopsy; Blood; Canis familiaris; Cells; Cellular Immunity; Child; Childhood Solid Neoplasm; Chronic; Client; Clinical Trials; Data; Dendritic Cells; Diagnosis; Disease; Disease-Free Survival; Dose; FDA approved; Formulation; Hour; Human; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunologics; Immunotherapeutic agent; Immunotherapy; Interferons; Long-Term Survivors; Lung; Malignant Neoplasms; Mediating; Messenger RNA; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Oncology; Outcome Measure; Pathway interactions; Patients; Penetration; Phase; Population; Production; RNA; Recurrence; Research Design; Resistance; Safety; Serum; Small Interfering RNA; T cell response; Testing; Therapeutic Effect; Toxic effect; Tumor Antigens; Tumor-Derived; Vaccine Therapy; Vaccines; Viremia; Work; adaptive immune response; adaptive immunity; arm; blood-based biomarker; canine model; cohort; comparative; design; engineering design; exome; immunogenic; immunoregulation; lipid nanoparticle; macrophage; nanoparticle; new technology; novel; osteosarcoma; programmed cell death ligand 1; resistance mechanism; response; response biomarker; siRNA delivery; single cell sequencing; therapy resistant; tumor; tumor microenvironment; vaccine response

Project Summary Immunotherapy has shown profound benefit for adult patients but has yet to be fully unlocked for pediatric solid tumors such as osteosarcoma (OSA) where a significant percentage of children/adolescents succumb due to the presence of lung metastasis. OSA, like many poorly tumor immunogenic tumors, is defined by a lack of tumor specific targets and a regulatory tumor microenvironment (TME). Unleashing immunotherapy against poorly immunogenic cancers requires new technologies that activate the TME, while concomitantly engaging both innate and adaptive arms of the immune system to generate sustained cellular immunity. We have developed a novel (FDA approved) RNA-nanoparticle (RNA-NP) vaccine that simultaneously penetrates/reprograms the TME while inducing an OSA specific T cell response. This vaccine utilizes a novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle (NP) “onion-like” package. We have shown that systemic administration of RNA-NPs safely mimics viremia, activating the quiescent immune system in only a few hours for induction of potent anti-tumor efficacy in several poorly immunogenic murine tumors resistant to immune checkpoint inhibitors. These RNA-NPs activate dendritic cells (DCs) that supplant regulatory intratumoral myeloid populations inducing antigen-recall response with long-term survivor benefits in murine metastatic pulmonary OSA models. We have established safety of RNA-NPs in acute/chronic murine toxicity studies, and launched a large animal canine OSA trial which demonstrated that RNA-NP administration is feasible, safe and immunologically active. While RNA-NPs mediate substantial anti-tumor activity, some animals suffer tumor outgrowth that warrant exploration of resistance mechanisms in our non-survivors. We have shown that RNA-NPs can be enriched for tumor specific antigens or configured with siRNAs to target pertinent regulatory axes (i.e. PD-L1), which can be studied in our murine/canine OSA models. The scientific premise for this work is that osteosarcoma is encased by a regulatory myeloid microenvironment that actively subverts adaptive immunity. We hypothesize that myeloid reprogramming of metastatic OSA will lead to safe eradication of disease. Our SPECIFIC AIMS are: 1. Establish mechanisms of OSA treatment resistance that can be overcome with adaptable RNA-NPs. 2. Identify correlates for vaccine response and escape in a comparative oncology canine OSA model. 3. Conduct a multi-institutional phase I/II study evaluating the safety and activity of the most promising RNA-NP formulation in recurrent OSA patients. Successful completion of this study will lead to a novel OSA therapy and a mechanistic understanding of its therapeutic effects that will be co-opted as biologic response correlates in a human clinical trial. .

项目概要 免疫疗法已显示出对成年患者的深远益处，但尚未完全释放对儿科实体瘤的疗效。 骨肉瘤 (OSA) 等肿瘤，其中很大一部分儿童/青少年因以下原因死亡 与许多低免疫原性肿瘤一样，OSA 的存在是由于缺乏肿瘤而定义的。 特定靶点和调节肿瘤微环境（TME）的免疫疗法。 免疫原性癌症需要激活 TME 的新技术，同时同时结合两者 免疫系统的先天性和适应性武器产生持续的细胞免疫。 我们开发了一种新型（FDA 批准）RNA 纳米颗粒 (RNA-NP) 疫苗，同时 穿透/重新编程 TME，同时诱导 OSA 特异性 T 细胞反应。 我们拥有将肿瘤来源的 mRNA 分层到脂质纳米颗粒 (NP)“洋葱状”包装中的工程设计。 研究表明，全身注射 RNA-NP 可以安全地模拟病毒血症，激活静止的免疫系统 只需几个小时即可在几种免疫原性较差的小鼠肿瘤中诱导出有效的抗肿瘤功效 这些 RNA-NP 会激活取代调节的树突状细胞 (DC)。 瘤内骨髓细胞群诱导抗原回忆反应，对小鼠具有长期幸存者益处 我们已经确定了 RNA-NP 在急性/慢性小鼠毒性中的安全性。 研究，并启动了一项大型动物犬 OSA 试验，证明 RNA-NP 给药是 可行、安全且具有免疫活性 虽然 RNA-NP 具有显着的抗肿瘤活性，但在某些动物中。 我们已经证明，患有肿瘤生长的人需要探索非幸存者的耐药机制。 RNA-NP 可以富集肿瘤特异性抗原，或者配置 siRNA 以靶向相关抗原 调节轴（即 PD-L1），可以在我们的鼠/犬 OSA 模型中进行研究 的科学前提。 这项工作是骨肉瘤被一个调节性骨髓微环境包裹着，该微环境主动颠覆 我们认为转移性 OSA 的骨髓重编程将导致安全根除。 我们的具体目标是： 1. 建立可通过适应性 RNA-NP 克服的 OSA 治疗耐药机制。 2. 确定比较肿瘤学犬 OSA 模型中疫苗反应和逃逸的相关性。 3. 进行多机构 I/II 期研究，评估最有前途的药物的安全性和活性 RNA-NP 制剂用于复发性 OSA 患者。 这项研究的成功完成将带来一种新颖的 OSA 疗法并对其机制有一个了解。 治疗效果将被选为与人体临床试验中的生物反应相关的治疗效果。 。