Engineered Nano-formulations for STING Activation

摘要 头颈部鳞状细胞癌(HNSCC)是一种侵袭性极强的疾病，总体生存率较低。 尽管免疫检查点阻断(ICB)取得了成功，但目前形式的免疫治疗受益较少 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。SING(干扰素基因的刺激物)被认为是一种关键的免疫调节剂，可以 将非响应者转换为响应者。鉴于刺痛通路在癌症免疫中的关键作用，许多 制药公司正在竞相建立他们的刺痛激动剂的发现管道。然而， 传统的刺痛激动剂有很大的局限性。现在临床试验中的大多数刺痛激动剂都是给药的 由于其药学性质较差，可通过瘤内注射。这排除了它们对 转移性癌症的治疗。因此，迫切需要寻找和开发新的刺激剂。 可以以有效和安全的方式消除晚期癌症。在这里，我们建议开发下一个- 产生具有强大的抗肿瘤功效、良好的药学性能的STING激动剂纳米粒， 和可接受的安全配置文件。我们将开发基于STING激动剂的新型治疗药物，并对其进行评估 在高级动物模型中的疗效和执行大型动物毒性研究。

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.