Engineered Nano-formulations for STING Activation

用于 STING 激活的工程纳米制剂

• 批准号: 10539415
• 负责人: Yu Leo Lei
• 金额: $ 57.47万
• 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/10539415
• 关键词: Address; Advanced Malignant Neoplasm; Animal Model; Animals; Benchmarking; Biological Response Modifiers; Cancer Patient; Canis familiaris; Cells; Clinical Trials; Data; Dental; Dinucleoside Phosphates; Disease; Disseminated Malignant Neoplasm; Dose; Engineering; Excision; Formulation; Genes; Genetic Engineering; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune response; Immune system; Immunization; 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; STING agonists; Safety; Sampling; Serum; Spleen; Stimulator of Interferon Genes; System; The Sun; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Tumor Immunity; anti-PD-1; anti-PD1 therapy; antitumor effect; base; 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 头颈鳞状细胞癌（HNSCC）是一种侵袭性极强的疾病，总体生存率较差。 尽管免疫检查点阻断 (ICB) 取得了成功，但当前形式的免疫疗法的获益却较少 超过 15% 的 HNSCC 患者。因此，迫切需要新的战略来实现强大的 免疫反应。 STING（干扰素基因刺激剂）被认为是关键的免疫调节剂之一 将非响应者转变为响应者。鉴于 STING 通路在癌症免疫中的关键作用，许多人 制药公司正在竞相建立 STING 激动剂的研发管线。然而， 传统的 STING 激动剂有很大的局限性。目前临床试验中大多数 STING 激动剂均已给药 由于其药物特性较差，因此通过瘤内注射进行。这排除了它们的适用性 治疗转移性癌症。因此，迫切需要识别和开发新的STING激动剂 可以有效、安全地消除晚期癌症。在这里，我们建议开发下一个—— 新一代 STING 激动剂纳米颗粒，具有强大的抗肿瘤功效，良好的药物特性， 和可接受的安全概况。我们将开发新型基于 STING 激动剂的疗法并评估其 在先进动物模型中的疗效并进行大型动物毒性研究。