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: 10650873
• 负责人: John Tanner Wilson
• 金额: $ 63.23万
• 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/10650873
• 关键词: Acceleration; 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; Enhancement Technology; Formulation; Foundations; Gene Activation; Generations; Half-Life; Immune; Immune Evasion; Immunocompetent; Immunologic Memory; Immunologic Stimulation; 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; Precipitation; Prognosis; Property; Protocols documentation; Recurrence; Recurrent disease; Regimen; Reproducibility; Research; Safety; Science; Signal Transduction; Site; Solid Neoplasm; Stimulator of Interferon Genes; T cell infiltration; T-cell inflamed; Therapeutic; Toxic effect; Translating; Translations; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tumor Immunity; Vesicle; Work; advanced disease; cancer cell; chimeric antigen receptor T cells; clinical translation; design; experience; fabrication; high risk; human disease; immune checkpoint blockade; immunoengineering; immunogenicity; improved; manufacturing process; materials science; mouse model; multidisciplinary; multimodality; nano; 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.

项目摘要 该提案解决了开发和转化儿童新疗法的重大未满足需求， 晚期高危神经母细胞瘤神经母细胞瘤（NB）是第三常见的儿科癌症， 儿童最常见的颅外实体瘤，占所有儿童癌症死亡的15%， 一年，尽管密集，多模式和有毒的治疗方案。免疫疗法提供了 选择性靶向和杀死癌细胞，并代表了根除复发性， 转移性疾病和实现具有最小毒性的持久治愈。然而，NB已被证明不佳 对大多数免疫方式有反应，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NB免疫疗法。这项建议的目的是 先进和成熟的STING激活纳米颗粒（斯坦斯），一种有前途的实验免疫制剂 纳米医学用于增强NB中的免疫治疗反应，走向临床转化。为了实现这一点， 我们将通过进一步优化斯坦斯， 通过可扩展的制造工艺， 免疫药理学参数在严格的NB小鼠模型，并建立合理设计的 免疫治疗方案，产生强大和持久的反应。我们将通过 遵循具体目标。首先，我们将采用综合的聚合物和材料科学方法， 通过简易和可扩展的快速纳米沉淀法， 纳米纤维战略其次，我们将评估药代动力学、生物分布、药效学， 斯坦斯在模拟人类疾病的严格免疫活性NB中的安全性和治疗功效。 第三，我们将评估和优化合理设计的免疫治疗方案， 免疫检查点阻断和NB靶向CAR T细胞。我们希望拟议的工作能够解决几个问题， 关键的临床前差距，填补后，将加速斯坦斯向临床转化。因此本 研究通过推进下一代纳米技术来解决高度临床紧迫性的问题， 增强NB中的免疫治疗应答。