Expanding the Therapeutic Window of Nanoparticle STING Agonists for Cancer Immunotherapy

项目摘要 免疫检查点阻断（ICB）是一种免疫疗法，正在彻底改变癌症治疗，但 对少数患者有效。在许多癌症类型中，这在很大程度上可以归因于缺乏足够的 定位用于通过ICB抗体再活化的肿瘤浸润性T细胞的数量或功能。因此有 迫切需要增加肿瘤免疫原性的策略，从而导致更多的患者， 受益于免疫疗法。我们的长期研究目标是通过以下方式改善对免疫疗法的反应： 利用抗肿瘤先天免疫的内源性机制的材料的分子工程。到 为此，我们开发了STING激活纳米颗粒（STING-NPs）-一类新的内体- 增强环二核苷酸（CDN）的胞质递送的去稳定化聚合物囊泡（聚合物囊泡） 干扰素基因刺激物（STING）途径的激动剂。CDN具有较差的药物样性质， 因此，细胞靶向性差，清除迅速，向胞质溶胶的转运效率低 STING是本地化的。这将CDN的临床评价限制在局部、肿瘤内给药， 这对于许多患有晚期播散性疾病的癌症患者是不可行的。STING-NP增强了 CDN的效力提高了几个数量级，导致肿瘤免疫原性增加， 肿瘤生长和改善对ICB的反应。我们在R 01应用中的目标是进一步扩展 STING-NP的效用和治疗窗口，通过1）优化它们的性质，以安全有效地系统性地 通过静脉内途径给药，和2）设计新的组合疗法，利用其 免疫药理学特性，以改善黑色素瘤模型中的免疫治疗应答， 对ICB有抵抗力。我们将通过以下具体目标来实现这一目标。首先，我们将重新设计 聚合物体冠以优化静脉内施用的药物的药代动力学和生物分布特征 STING-NP在肿瘤微环境中实现最大CDN递送和STING活化。第二、 我们将合成一类新的修饰的CDN，其在结构上优化以增加掺入， 保留到STING-NP，并将研究CDN结构，负载和稳定性对 免疫刺激活性和治疗功效。第三，我们将开发合理设计和临床 靶向STING激动剂抗性机制的相关化疗和免疫疗法组合 我们最近发现的。总的来说，这些研究将推动STING-NP作为一个平台， 肿瘤免疫原性和改善免疫治疗的结果。在这样做的同时，这些调查还将 推进我们对纳米载体性质，药理学行为， 抗肿瘤免疫、治疗活性和毒性，有可能为广泛应用的设计标准提供信息。 适用于STING和其他先天免疫激动剂。

PROJECT SUMMARY Immune checkpoint blockade (ICB) is an immunotherapy that is revolutionizing cancer treatment, but is effective in a minority of patients. Across many cancer types, this can largely be ascribed to an insufficient number or function of tumor infiltrating T cells positioned for reactivation by ICB antibodies. Therefore, there is a critical need for strategies to increase tumor immunogenicity that results in a greater number of patients that benefit from immunotherapy. Our long-term research goal is to improve responses to immunotherapy through the molecular engineering of materials that harness endogenous mechanisms of antitumor innate immunity. To that end, we have developed STING-activating nanoparticles (STING-NPs) – a new class of endosome- destabilizing polymer vesicles (polymersomes) that enhance the cytosolic delivery of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway. CDNs have poor drug-like properties and therefore suffer from poor cellular targeting, rapid clearance, and inefficient transport to the cytosol where STING is localized. This has restricted clinical evaluation of CDNs to local, intratumoral administration, which is not feasible for many cancer patients with advanced disseminated disease. STING-NPs enhance the potency of CDNs by several orders of magnitude, resulting in increased tumor immunogenicity, inhibition of tumor growth, and improved response to ICB. Our objective in this R01 application is to further expand the utility and therapeutic window of STING-NPs by 1) optimizing their properties for safe and effective systemic administration via an intravenous route, and 2) designing new combination therapies that leverage their immunopharmacological properties to improve immunotherapy responses in melanoma models that are resistant to ICB. We will accomplish this through the following Specific Aims. First, we will re-engineer the polymersome corona to optimize the pharmacokinetics and biodistribution profile of intravenously administered STING-NP to achieve maximal CDN delivery and STING activation in the tumor microenvironment. Second, we will synthesize a new class of modified CDNs that are structurally optimized for increased incorporation and retention into STING-NPs, and will investigate the effect of CDN structure, loading, and stability on immunostimulatory activity and therapeutic efficacy. Third, we will develop rationally designed and clinically relevant chemo- and immunotherapy combinations that target mechanisms of resistance to STING agonists that we have recently identified. Overall, these studies will advance STING-NPs as a platform for increasing tumor immunogenicity and improving outcomes of immunotherapy. In doing so, these investigations will also advance our understanding of relationships between nanocarrier properties, pharmacological behavior, antitumor immunity, therapeutic activity, and toxicity with potential to inform design criteria that are broadly applicable to STING and other innate immune agonists.