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 该提案涉及为患有儿童开发和翻译新疗法的重要，未满足的需求 高危，高危神经母细胞瘤。神经母细胞瘤（NB）是第三大儿科癌症，是 最常见的儿童颅外实体瘤，占所有儿科癌症死亡的15％ 一年，尽管有密集，多模式和有毒治疗方案。免疫疗法为 选择性靶向和杀死癌细胞，代表了消除复发的有吸引力的替代方法 转移性疾病并达到耐用的毒性耐用性。但是，NB证明很差 对大多数免疫治疗方式的反应，特别是包括免疫检查点封锁和CAR T 细胞疗法。因此，必须开发新的NB免疫疗法。该提议的目的是 提前和成熟的刺激激活纳米颗粒（Stans），这是一种有希望的实验性免疫治疗性 纳米医学，用于增强NB的免疫疗法反应，对临床翻译。为此， 我们将直接解决Stans临床发展的潜在障碍，通过进一步优化其 通过可扩展的制造过程，生理化学和生物学特性，阐明钥匙 严格的NB小鼠模型中的免疫药理学参数，并建立合理设计的 产生健壮耐用反应的免疫疗法方案。我们将通过 遵循特定目标。首先，我们将采用集成的聚合物和材料科学方法来 可重现性通过简便而可扩展的闪光沉淀进行优化的特性制造Stans 纳米制造策略。第二，我们将评估药代动力学，生物分布，药效学， Stans在模仿人类疾病的严格免疫能力NB中的安全性和治疗功效。 第三，我们将评估并优化合理设计的免疫治疗方案，将Stans与 免疫检查点阻滞和靶向NB的CAR T细胞。我们希望拟议的工作能够解决几个 关键的临床前差距在填充后会加速Stans朝着临床翻译。因此，这个 研究通过推进下一代纳米技术来解决高临床紧迫性的问题 增强NB中的免疫疗法反应。