Expanding the Therapeutic Window of Nanoparticle STING Agonists for Cancer Immunotherapy

扩大纳米颗粒 STING 激动剂用于癌症免疫治疗的治疗窗口

• 批准号: 10600077
• 负责人: John Tanner Wilson
• 金额: $ 35.74万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-21 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600077
• 关键词: Address; Affinity; Agonist; Antibodies; Behavior; Biodistribution; Biological; CD276 gene; Cancer Patient; Circulation; Clinical; Clinical Treatment; Combination immunotherapy; Cross-Priming; Cytosol; Development; Dinucleoside Phosphates; Disease; Drug Delivery Systems; Drug Kinetics; Endosomes; Engineering; Gene Activation; Generations; Goals; Half-Life; Immune; Immune checkpoint inhibitor; Immune response; Immunologic Memory; Immunooncology; Immunotherapeutic agent; Immunotherapy; Infiltration; Intravenous; Investigation; Ligands; Lipids; Minority; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Nanotechnology; Natural Immunity; Nature; Pathway interactions; Patients; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Polymers; Population; Positioning Attribute; Prodrugs; Property; Publishing; Recurrent disease; Regimen; Research; Resistance; Route; Science; Sentinel Lymph Node; Stimulator of Interferon Genes; Structure; Structure-Activity Relationship; T-Lymphocyte; T-cell inflamed; Therapeutic; Therapeutic Uses; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; Vesicle; cancer immunotherapy; cancer infiltrating T cells; cancer therapy; cancer type; cellular targeting; clinical translation; clinically relevant; design; immune activation; immune checkpoint; immune checkpoint blockade; immune resistance; immunoengineering; immunogenicity; improved; improved outcome; innovation; insight; intravenous administration; melanoma; multidisciplinary; nanocarrier; nanoparticle; new combination therapies; novel; novel strategies; pharmacologic; phosphoric diester hydrolase; preclinical development; rational design; recruit; research clinical testing; resistance mechanism; response; restraint; small molecule inhibitor; success; targeted treatment; therapeutic target; treatment response; tumor; tumor growth; tumor immunology; tumor microenvironment; uptake

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.

项目总结 免疫检查点阻断(ICB)是一种正在给癌症治疗带来革命性变化的免疫疗法，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 被ICB抗体激活的肿瘤浸润性T细胞的数量或功能。因此，有 迫切需要提高肿瘤免疫原性的策略，从而导致更多的患者 从免疫疗法中受益。我们的长期研究目标是通过以下途径提高对免疫疗法的反应 利用抗肿瘤先天免疫的内源性机制的材料的分子工程。至 为此，我们开发出了刺激性纳米颗粒(STING-NPs)--一种新型的内吞体体-- 增强环二核苷酸(CDN)胞质递送的不稳定聚合物小泡(聚合体) 干扰素基因刺激物(STING)途径激动剂。CDN的类药物特性较差， 因此细胞靶向性差，清除速度快，向胞浆的转运效率低 斯汀是本地化的。这限制了CDN的临床评估仅限于局部、肿瘤内给药， 这对许多患有晚期播散性疾病的癌症患者来说是不可行的。刺痛-NPs增强了 CDN的效力提高了几个数量级，从而增强了肿瘤的免疫原性，抑制了 肿瘤生长，以及对ICB的反应改善。我们在此R01应用程序中的目标是进一步扩展 通过1)优化其性能以实现安全有效的全身用药和治疗窗口 通过静脉给药，以及2)设计新的联合疗法，利用他们的 提高黑色素瘤模型免疫治疗反应的免疫药理学特性 对ICB的抗性。我们将通过以下具体目标实现这一目标。首先，我们将重新设计 多聚体冠脉优化静脉给药的药代动力学和生物分布 STIN-NP在肿瘤微环境中实现CDN的最大传递和STING的激活。第二, 我们将合成一类新的修饰CDN，这些CDN在结构上进行了优化，以增加掺入和 并将研究CDN的结构、负载和稳定性对其的影响 免疫刺激活性和治疗效果。第三，合理设计和临床应用。 针对刺痛激动剂抵抗机制的相关化疗和免疫治疗组合 我们最近发现的。总体而言，这些研究将推动刺痛-NPs作为一个平台，以增加 肿瘤的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 促进我们对纳米载体特性、药理行为、 抗肿瘤免疫、治疗活性和毒性，有可能成为广泛的设计标准 适用于刺痛和其他天然免疫激动剂。

项目成果

Bioinspired vaccines to enhance MHC class-I antigen cross-presentation.

• DOI: 10.1016/j.coi.2022.102215
• 发表时间: 2022-08
• 期刊: Current opinion in immunology
• 影响因子: 7

Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy.

• DOI: 10.1021/acs.chemrev.1c00750
• 发表时间: 2022-03-23
• 期刊: Chemical reviews
• 影响因子: 62.1
• 作者: Garland KM;Sheehy TL;Wilson JT
• 通讯作者: Wilson JT

Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists.

两亲聚电解质移植物共聚物增强了环状二核苷酸刺痛激动剂的活性。

• DOI: 10.1002/adhm.202001056
• 发表时间: 2021-01
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Nguyen DC;Shae D;Pagendarm HM;Becker KW;Wehbe M;Kilchrist KV;Pastora LE;Palmer CR;Seber P;Christov PP;Duvall CL;Wilson JT
• 通讯作者: Wilson JT