Toward Translation of an Immunotherapeutic Nanomedicine for Neuroblastoma

神经母细胞瘤免疫治疗纳米药物的转化

• 批准号: 10529900
• 负责人: John Tanner Wilson
• 金额: $ 60.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10529900
• 关键词: Accounting; Address; Adult; Agonist; Animal Model; Biodistribution; Biological; CAR T cell therapy; Cessation of life; Child; Childhood Extracranial Solid Tumor; Childhood Solid Neoplasm; Clinic; Clinical; Combination immunotherapy; Combined Modality Therapy; Cytosol; Data; Development; Dinucleoside Phosphates; Disease; Drug Delivery Systems; Drug Kinetics; Formulation; Foundations; Gene Activation; Generations; Half-Life; Immune; Immunization; Immunocompetent; Immunologic Memory; Immunologics; Immunooncology; Immunotherapeutic agent; Immunotherapy; Industrialization; Malignant Childhood Neoplasm; Methods; Modality; Modeling; Molecular Weight; Nanotechnology; Natural Immunity; Neoplasm Metastasis; Neuroblastoma; Outcome; Particle Size; Pathway interactions; Patients; Pediatric Oncology; Periodicity; Pharmacodynamics; Pharmacologic Substance; Plasma; Polymers; Prognosis; Property; Protocols documentation; Recurrence; Regimen; Reproducibility; Research; Safety; Science; Signal Transduction; Site; Solid Neoplasm; Stimulator of Interferon Genes; T-cell inflamed; Therapeutic; Toxic effect; Translating; Translations; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tumor Immunity; Tumor-infiltrating immune cells; Vesicle; Work; advanced disease; base; cancer cell; chimeric antigen receptor T cells; clinical translation; design; experience; high risk; human disease; immune checkpoint blockade; immunoengineering; immunogenicity; improved; manufacturing process; materials science; mouse model; multidisciplinary; multimodality; nanofabrication; nanomedicine; nanoparticle; next generation; novel; novel therapeutics; pre-clinical; preclinical development; preclinical evaluation; prevent; programs; rational design; response; systemic toxicity; therapeutic target; treatment response; tumor; tumor growth; tumor immunology; tumor microenvironment; uptake

PROJECT SUMMARY This proposal addresses the significant, unmet need to develop and translate new therapies for children with advanced, high-risk neuroblastoma. Neuroblastoma (NB) is the third most common pediatric cancer and the most common extracranial solid tumor of childhood, accounting for 15% of all pediatric cancer deaths each year despite an intensive, multimodal, and toxic treatment regimen. Immunotherapy offers the potential for selective targeting and killing of cancer cells and represents an appealing alternative for eradicating recurrent, metastatic disease and achieving durable cures with minimal toxicity. However, NB has proven poorly responsive to most immunotherapeutic modalities, notably including immune checkpoint blockade and CAR T cell therapy. Therefore, novel immunotherapies for NB must be developed. The objective of this proposal is to advance and mature STING-activating nanoparticles (STANs), a promising experimental immunotherapeutic nanomedicine for enhancing immunotherapy responses in NB, towards clinical translation. To accomplish this, we will directly address potential barriers to the clinical advancement of STANs by further optimizing their physiochemical and biological properties via a scalable manufacturing process, elucidating key immunopharmacological parameters in rigorous NB mouse models, and establishing rationally-designed immunotherapy regimens that generate robust and durable responses. We will accomplish this through the following Specific Aims. First, we will employ an integrated polymer and materials science approach to reproducibility fabricate STANs with optimized properties via a facile and scalable flash nanoprecipitation nanofabrication strategy. Second, we will evaluate the pharmacokinetics, biodistribution, pharmacodynamics, safety, and therapeutic efficacy of STANs in a rigorous immunocompetent NB that mimic human disease. Third, we will evaluate and optimize rationally-designed immunotherapy regimens combining STANs with immune checkpoint blockade and NB-targeted CAR T cells. We expect the proposed work to address several critical preclinical gaps that, when filled, will accelerate STANs toward clinical translation. Therefore, this research addresses a problem of high clinical urgency by advancing a next-generation nanotechnology for enhancing immunotherapy responses in NB.

项目总结 这项建议解决了尚未得到满足的重大需求，即开发和翻译针对儿童的新疗法 晚期高危神经母细胞瘤。神经母细胞瘤(NB)是儿童第三常见的癌症， 儿童最常见的颅外实体瘤，占所有儿童癌症死亡的15% 尽管采取了密集、多式联运和有毒的治疗方案，但仍是一年。免疫疗法提供了潜在的 选择性靶向和杀死癌细胞，是根除复发的一种有吸引力的替代方案， 转移疾病，以最小的毒性实现持久的治愈。然而，事实证明，NB表现不佳 对大多数免疫治疗方式有反应，特别是包括免疫检查点阻断和CAR T 细胞疗法。因此，必须开发新的针对NB的免疫治疗方法。这项建议的目的是 一种有前景的实验性免疫疗法--成熟的刺激性纳米粒(STAN) 纳米药物用于增强神经母细胞瘤的免疫治疗反应，临床翻译。要做到这一点， 我们将直接解决STAN临床进展的潜在障碍，通过进一步优化其 通过可扩展的制造工艺获得物理化学和生物特性，阐明关键 严谨的NB小鼠模型的免疫药理参数，并建立合理设计 免疫治疗方案，产生强大和持久的反应。我们将通过以下方式实现这一目标 遵循特定的目标。首先，我们将采用聚合物和材料科学的综合方法来 重复性通过简单且可扩展的闪光纳米沉淀法制造具有优化性能的STAN 纳米制造战略。第二，我们将评估药物动力学，生物分布，药效学， 在模拟人类疾病的严格免疫活性NB中STANS的安全性和治疗效果。 第三，我们将评估和优化合理设计的联合STANS和 免疫检查点阻断和NB靶向CAR T细胞。我们预计拟议的工作将涉及几个 关键的临床前空白，一旦填补，将加速STAS向临床转化。因此，这 研究通过推进下一代纳米技术来解决临床上高度紧迫的问题 增强NB患者的免疫治疗反应。