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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该提案解决了为患有以下疾病的儿童开发和转化新疗法的重大但未满足的需求晚期、高危神经母细胞瘤。神经母细胞瘤 (NB) 是第三大常见的儿科癌症，儿童最常见的颅外实体瘤，占所有儿童癌症死亡的 15% 尽管采取了强化、多模式和有毒的治疗方案，但仍持续了一年。免疫疗法提供了潜力选择性靶向和杀死癌细胞，是根除复发性、转移性疾病并以最小的毒性实现持久治愈。但事实证明NB效果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，必须开发针对 NB 的新型免疫疗法。该提案的目的是先进且成熟的 STING 激活纳米粒子 (STAN)，一种有前途的实验性免疫治疗药物用于增强 NB 免疫治疗反应的纳米药物，走向临床转化。为了实现这一目标，我们将通过进一步优化 STAN 来直接解决 STAN 临床进展的潜在障碍通过可扩展的制造工艺来研究理化和生物特性，阐明关键严格的 NB 小鼠模型中的免疫药理学参数，并建立合理设计的产生强烈和持久反应的免疫治疗方案。我们将通过以下方式实现这一目标遵循具体目标。首先，我们将采用综合聚合物和材料科学方法通过简单且可扩展的闪速纳米沉淀法可再现性地制造具有优化性能的 STAN 纳米制造策略。其次，我们将评估药代动力学、生物分布、药效学、 STAN 在模拟人类疾病的严格免疫功能的 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STANs与免疫治疗方案相结合的免疫治疗方案。免疫检查点阻断和 NB 靶向 CAR T 细胞。我们期望拟议的工作能够解决几个问题关键的临床前空白一旦被填补，将加速 STAN 走向临床转化。因此，这研究通过推进下一代纳米技术解决了临床高度紧迫的问题增强 NB 的免疫治疗反应。