Engineered Nano-formulations for STING Activation

用于 STING 激活的工程纳米制剂

• 批准号: 10661091
• 负责人: Yu Leo Lei
• 金额: $ 57.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-06 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661091
• 关键词: Address; Advanced Malignant Neoplasm; Agonist; Animal Model; Animals; Benchmarking; Biological Response Modifiers; Breeding; Cancer Patient; Canis familiaris; Cells; Clinical Trials; Crystal Formation; Data; Dental; Dinucleoside Phosphates; Disease; Disseminated Malignant Neoplasm; Dose; Engineering; Excision; Formulation; Gene Activation; Genes; Genetic Engineering; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune response; Immune system; Immunologic Stimulation; Immunotherapy; In Vitro; Injections; Interferons; Knowledge; Libraries; Lymphoid Tissue; Malignant Neoplasms; Manganese; Mediating; Modeling; Mus; National Institute of Dental and Craniofacial Research; Nature; Neoplasm Metastasis; Oral; Pathway interactions; Patients; Periodicity; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Property; Public Health; Race; Rattus; Research; Resistance; Role; Safety; Sampling; Serum; Spleen; System; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Tumor Immunity; anti-PD-1; anti-PD1 therapy; antitumor effect; craniofacial; design; efficacy evaluation; immune activation; immune checkpoint blockade; immunomodulatory strategy; immunoregulation; intravenous administration; malignant mouth neoplasm; mouse model; nano; nanocrystal; nanoengineering; nanoformulation; nanomaterials; nanoparticle; new technology; next generation; novel; particle; particle therapy; response; success; tumor

Abstract Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive disease with poor overall survival. Despite the success of immune checkpoint blockade (ICB), the current forms of immunotherapy benefit only less than 15% of HNSCC patients. Therefore, there exists a critical need for new strategies for achieving powerful immune responses. STING (stimulator of IFN genes) is considered one of the key immune regulators that could convert non-responders to responders. Given the critical role of the STING pathway in cancer immunity, many pharmaceutical companies are racing to establish their discovery pipelines for STING agonists. However, conventional STING agonists have major limitations. Most STING agonists in clinical trials now are administrated via intratumoral injection due to their poor pharmaceutical properties. This precludes their applicability for the treatment of metastatic cancer. Therefore, there is an urgent need to identify and develop new STING agonists that can eliminate advanced cancer in an effective and safe manner. Here, we propose to develop the next- generation STING agonist nanoparticles with potent anti-tumor efficacy, favorable pharmaceutical properties, and acceptable safety profiles. We will develop novel STING agonist-based therapeutics and evaluate their efficacy in advanced animal models and perform large animal toxicity studies.

抽象的 头颈部鳞状细胞癌（HNSCC）是一种极为侵略性的疾病，总生存率较差。 尽管免疫检查点封锁（ICB）成功，但当前的免疫疗法形式受益于较少的好处 超过15％的HNSCC患者。因此，存在实现强大的新策略的迫切需求 免疫反应。 sting（IFN基因的刺激剂）被认为是可以的关键免疫调节剂之一 将非反应者转换为响应者。鉴于刺痛途径在癌症免疫中的关键作用，许多 制药公司正在竞赛建立他们的发现管道，以刺激激动剂。然而， 常规的刺痛激动剂有重大局限性。现在，临床试验中的大多数刺痛激动剂是管理的 由于其药物差而导致的肿瘤内注射。这排除了他们对 转移性癌症的治疗。因此，迫切需要识别和发展新的刺痛激动剂 这可以以有效且安全的方式消除晚期癌症。在这里，我们建议开发下一个 具有有效的抗肿瘤功效，有利的药物特性的生成刺激性激动剂纳米颗粒 和可接受的安全概况。我们将开发基于激动剂的刺激性疗法，并评估他们的 晚期动物模型的功效并进行大型动物毒性研究。