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。

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.