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 免疫疗法已显示出对成人患者的巨大益处，但尚未完全解锁儿科固体 骨肉瘤（OSA）等肿瘤，其中很大一部分儿童/青少年因骨肉瘤而死亡 肺转移的存在。与许多肿瘤免疫原性差的肿瘤一样，OSA的定义是缺乏肿瘤免疫原性。 特异性靶点和调节性肿瘤微环境（TME）。释放免疫疗法， 免疫原性癌症需要新的技术来激活TME，同时同时使两者都参与其中。 免疫系统的先天和适应性武器，以产生持续的细胞免疫。 我们已经开发了一种新的（FDA批准的）RNA纳米颗粒（RNA-NP）疫苗， 在一些实施方案中，所述细胞可以穿透/重编程TME，同时诱导OSA特异性T细胞应答。这种疫苗利用了一种新的 这是一种将肿瘤来源的mRNA分层到脂质纳米颗粒（NP）“洋葱样”包装中的工程设计。我们有 显示RNA-NPs的全身给药安全地模拟病毒血症，激活静止的免疫系统 在几种免疫原性差的鼠肿瘤中诱导有效的抗肿瘤功效 对免疫检查点抑制剂有抵抗力。这些RNA-NP激活树突状细胞（DC），其取代了调节性免疫应答。 肿瘤内髓样细胞群诱导抗原回忆应答，对小鼠长期存活有益 转移性肺OSA模型。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，该试验证明RNA-NP给药是有效的。 可行的、安全的和免疫活性的。虽然RNA-NPs介导大量的抗肿瘤活性，但一些动物 遭受肿瘤生长，这需要探索我们非幸存者的耐药机制。我们已经表明 RNA-NP可以富集肿瘤特异性抗原或与siRNA一起配置以靶向相关的肿瘤特异性抗原。 调节轴（即PD-L1），可以在我们的鼠/犬OSA模型中进行研究。科学前提是 这项工作是，骨肉瘤是包裹着一个调节骨髓微环境，积极颠覆 适应性免疫我们假设转移性OSA的骨髓重编程将导致安全根除 疾病。我们的具体目标是： 1.建立可以用适应性RNA-NP克服的OSA治疗抗性机制。 2.在比较肿瘤学犬OSA模型中确定疫苗应答和逃逸的相关性。 3.进行多机构I/II期研究，评估最有希望的药物的安全性和活性。 复发性OSA患者中的RNA-NP制剂。 这项研究的成功完成将导致一种新的阻塞性睡眠呼吸暂停治疗和其机制的理解， 在人体临床试验中，将作为生物学反应相关性的治疗效果。 .