Intrapleural immunotherapeutic nanoparticles for MPE treatment

用于 MPE 治疗的胸膜内免疫治疗纳米粒子

基本信息

批准号：
10673709
负责人：
Yong Lu
金额：
$ 44.92万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673709
关键词：
Address Agonist Antigen-Presenting Cells Binding Biological Biological Assay CD8-Positive T-Lymphocytes Cancer Patient Cells Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy Complex Cross-Priming Cytosol Cytotoxic T-Lymphocytes Data Dendritic Cells Drug Kinetics Environment Enzymes Foundations Gene Activation Gene Conversion Goals IgG1 Immune Immune Targeting Immune checkpoint inhibitor Immunity Immunologics Immunology procedure Immunophenotyping Immunotherapeutic agent Immunotherapy Incubated Inflammatory Injections Interferon Type I Ligation Liposomes Macrophage Malignant - descriptor Malignant Neoplasms Malignant Pleural Effusion Mediating Modeling Mus Natural Killer Cells Non-Small-Cell Lung Carcinoma Operative Surgical Procedures PD-1/PD-L1 Pathway interactions Patients Phenotype Phosphatidylserines Play Pleural cavity Predisposition Production Prognosis Property Rationalization Research Project Grants Role Sampling Secondary to Signal Transduction Solid Neoplasm Specificity Stimulator of Interferon Genes T cell infiltration T-Lymphocyte Testing Therapeutic Effect Tissues Toxic effect Treatment Efficacy Tumor Antigens Tumor Burden Tumor Immunity Tumor Promotion Work anti-PD-L1 anti-cancer antibody-dependent cell cytotoxicity calcium phosphate cancer immunotherapy chemotherapy clinical development cytotoxic effector T cell effusion fighting gene interaction immune checkpoint blockade improved in vivo insight interest lung cancer cell mouse model nanoparticle neoplastic cell novel palliative phosphoric diester hydrolase preclinical study response single-cell RNA sequencing standard of care targeted delivery therapeutic evaluation translational goal tumor tumor microenvironment tumor-immune system interactions uptake

项目摘要

Abstract Malignant pleural effusion (MPE) secondary to non-small cell lung cancer (NSCLC) represents a significant challenge in clinical patient management. MPE is commonly indicative of late stage malignancy and prognosis of MPE is extremely poor, with a median survival between 4-9 months. The presence of MPE often precludes surgical intervention, and many patients with MPE are not fit for chemotherapy due to the extremely poor condition. Current standard of care treatment for MPE is largely palliative. Significant clinical evidence suggests that the tumor immune microenvironment (TIME) of MPE is profoundly immunosuppressive with abundant tumor- promoting phenotype of immune cells, which impacts negatively on antitumor immunity. Previous attempts to improve the TIME involving intrapleural administration of immunotherapeutics have led to some degree of efficacy. The recent advent of immunotherapy with immune checkpoint blockade (ICB) has aroused renewed interest in seeking an effective strategy to mitigate the immune cold MPE to enhance the ICB immunotherapy. Stimulators of interferon genes (STING) pathway has recently been identified to play an important role on induction of antitumor immunity. As a potent STING agonist, cGAMP ligates STING in cytosol to activate type I interferons (IFNs) production. However, intrinsic property of cGAMP makes it susceptible to degradation by a phosphodiesterase that exists in many tissues, and higher levels of the enzyme are identified in malignant effusions. Moreover, previous studies indicate that activation of STING within tumor–resident antigen-presenting cells (APCs) is necessary for induction of tumor-specific CD8+T cell immunity. We have recently developed a novel nanotechonological strategy for APC-targeted delivery of cGAMP (LNP-STING). We assemble LNP- STING with phosphatidylserine on the outer layer of liposome to facilitate its recognition and uptake preferably by APCs, and load cGAMP complexed with calcium phosphate to enhance both the loading efficiency and the release of cGAMP to cytosol, where it binds to STING. In this project, we propose to establish an optimal LNP- STING for intrapleural administration and test if intrapleural LNP-STING converts the immune cold into proinflammatory hot MPE. Our central hypothesis is that intrapleural LNP-STING enables to mitigate the immunosuppressive MPE, thereby setting the stage for favorable response to anti-PD-L1 ICB. We will test the combination immunotherapy in both MPE mouse models and NSCLC patients’ MPE samples. We propose to establish an optimal LNP-STING for intrapleural APC-targeted delivery of STING agonist (Aim1). We will then determine if intrapleural LNP-STING effectively mitigate the immune cold MPE (Aim2). We will last determine if intrapleural LNP-STING enhances efficacy of the ICB immunotherapy (Aim3). More importantly, we will gain insights into the biological mechanisms of intrapleural LNP-STING in combination with anti-PD-L1 ICB, which likely engage both the innate and adaptive anticancer immunity. This work is significant because it may have a potential to make an impact on the MPE immunotherapy.

抽象的继发于非小细胞肺癌 (NSCLC) 的恶性胸腔积液 (MPE) 是一种重要的 MPE 是临床患者管理中的挑战，通常预示着晚期恶性肿瘤和预后。 MPE 的发生率极低，中位生存期为 4-9 个月。 MPE 的存在通常会导致患者无法生存。手术干预，许多MPE患者由于病情极差不适合化疗目前 MPE 的护理治疗标准主要是姑息治疗。 MPE 的肿瘤免疫微环境 (TIME) 具有严重的免疫抑制性，具有丰富的肿瘤- 促进免疫细胞的表型，这对之前的抗肿瘤免疫产生负面影响。改善涉及免疫治疗胸腔内给药的时间已导致一定程度的最近出现的免疫检查点阻断（ICB）免疫疗法引起了人们的关注。有兴趣寻求有效的策略来减轻免疫冷MPE以增强ICB免疫治疗。最近发现干扰素基因刺激物 (STING) 通路在作为一种有效的 STING 激动剂，cGAMP 在细胞质中连接 STING 以激活 I 型免疫。然而，cGAMP 的内在特性使其容易被干扰素 (IFN) 降解。磷酸二酯酶存在于许多组织中，并且在恶性肿瘤中发现该酶水平较高此外，先前的研究表明，肿瘤驻留抗原呈递中的 STING 被激活。细胞（APC）是诱导肿瘤特异性 CD8+T 细胞免疫所必需的。用于 APC 靶向递送 cGAMP 的新型纳米技术策略 (LNP-STING) 我们组装了 LNP-。脂质体外层带有磷脂酰丝氨酸的STING，有利于其识别和摄取通过APCs，负载与磷酸钙复合的cGAMP，以提高负载效率和 cGAMP 释放到细胞质中，并与 STING 结合。在这个项目中，我们建议建立一个最佳的 LNP-。用于胸膜内给药的 STING 并测试胸膜内 LNP-STING 是否将免疫冷转化为我们的中心假设是胸腔内 LNP-STING 能够减轻促炎性热 MPE。免疫抑制性 MPE，为抗 PD 的良好反应奠定了基础，从而使 ICB 成为可能。我们建议对 MPE 小鼠模型和 NSCLC 患者的 MPE 样本进行联合免疫治疗。然后，我们将建立一个最佳的 LNP-STING，用于胸膜内 APC 靶向递送 STING 激动剂（目标 1）。确定胸腔内 LNP-STING 是否能有效减轻免疫性冷 MPE（目标 2）。胸腔内 LNP-STING 增强了 ICB 免疫疗法的疗效（Aim3）。深入了解胸腔内 LNP-STING 与抗 PD-L1 ICB 组合的生物学机制，这项工作很可能涉及先天性和适应性抗癌免疫，因为它可能具有抗癌作用。可能对 MPE 免疫疗法产生影响。