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.

摘要 头颈部鳞状细胞癌（HNSCC）是一种侵袭性极强的疾病，总体生存率很低。 尽管免疫检查点阻断（ICB）取得了成功，但目前形式的免疫疗法受益较少 超过15%的HNSCC患者。因此，迫切需要制定新的战略， 免疫反应。STING（干扰素基因刺激因子）被认为是一种关键的免疫调节因子， 将无反应者转化为反应者。鉴于STING途径在癌症免疫中的关键作用，许多人认为， 制药公司正在竞相建立STING激动剂的发现管道。然而，在这方面， 常规的STING激动剂具有很大的局限性。现在临床试验中的大多数STING激动剂都是 由于它们的药物性质差，通过瘤内注射来治疗。这就排除了它们对 转移性癌症的治疗。因此，迫切需要鉴定和开发新的STING激动剂。 可以有效和安全地消除晚期癌症。在这里，我们建议开发下一个- 产生STING激动剂纳米颗粒，具有有效的抗肿瘤功效，有利的药学性质， 和可接受的安全性。我们将开发新的基于STING激动剂的治疗方法，并评估其疗效。 在先进的动物模型中的有效性，并进行大型动物毒性研究。