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. .

项目摘要 免疫疗法对成年患者显示出深远的好处，但尚未完全解锁儿科固体 诸如骨肉瘤（OSA）之类的肿瘤，在很大一部分儿童/青少年由于 肺转移的存在。 OSA与许多肿瘤免疫原性肿瘤一样，由缺乏肿瘤定义 特定靶标和调节性肿瘤微环境（TME）。释放免疫疗法对不良 免疫原性癌症需要激活TME的新技术，同时同时参与 免疫系统的先天和适应性臂，以产生持续的细胞免疫史。 我们已经开发了一种新颖（FDA批准）RNA纳米颗粒（RNA-NP）疫苗 穿透/重编程TME，同时诱导OSA特异性T细胞响应。这种疫苗利用小说 将肿瘤分层的工程设计将mRNA衍生成脂质 - 纳米颗粒（NP）“洋葱状”包装。我们有 表明全身施用RNA-NP可以安全地模仿病毒血症，激活静态免疫系统 在几个小时内，可以在几个不良免疫原性的鼠肿瘤中诱导有效的抗肿瘤效率 对免疫切除点抑制剂的抗性。这些RNA-NP激活了取代调节的树突状细胞（DC） 肿瘤内髓样群体诱导抗原核心反应，并具有长期幸存者的益处 转移性肺OSA模型。我们已经在急性/慢性鼠毒性中建立了RNA-NP的安全性 研究，并发起了一项大型动物犬OSA试验，该试验表明RNA-NP给药是 可行，安全且免疫学活跃。 RNA-NP介导了实质性的抗肿瘤活性，而某些动物 我们已经表明，肿瘤的生长需要探索我们非活物中的抗性机制。 可以将RNA-NP富含特异性抗原或配置siRNA的靶向相关性 调节轴（即PD-L1），可以在我们的鼠/犬OSA模型中进行研究。科学前提 这项工作是骨肉瘤被一种调节性髓样微环境所包围，该微环境积极颠覆 适应性免疫学。我们假设转移性OSA的髓样重编程将导致安全根除 疾病。我们的具体目的是： 1。建立可以通过适应性的RNA-NP克服OSA治疗耐药性的机制。 2。在比较肿瘤学OSA模型中确定疫苗反应的相关性并逃脱。 3.进行多机构的I/II阶段研究，以评估最有前途的安全性和活动 复发性OSA患者的RNA-NP公式。 这项研究的成功完成将导致一种新颖的OSA疗法及其对其的机械理解 在人类的临床试验中，将对生物学反应进行选择的治疗作用。 。