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.

抽象的非小细胞肺癌（NSCLC）继发的恶性胸腔积液（MPE）表示显着临床患者管理中的挑战。 MPE通常表示晚期恶性肿瘤和预后 MPE的较差，中位生存期在4-9个月之间。 MPE的存在通常无法手术干预，许多MPE患者由于极差而不适合化学疗法健康）状况。当前的MPE护理标准在很大程度上是姑息治疗的。大量临床证据表明 MPE的肿瘤免疫微环境（时间）具有深刻的免疫抑制作用，肿瘤丰富促进免疫细胞的表型，这对抗肿瘤免疫细胞产生负面影响。以前的尝试改善涉及免疫疗法经胸膜内给药的时间已导致一定程度效率。免疫障碍封锁（ICB）的免疫疗法最近发生的冒险已经引起了续签有兴趣寻求一种有效的策略来减轻免疫冷MPE以增强ICB免疫疗法。最近已经确定了干扰素基因（Sting）途径的刺激剂诱导抗肿瘤免疫力。作为潜在的刺痛激动剂，CGAMP将细胞质的刺带动刺激以激活I型干扰素（IFNS）生产。但是，CGAMP的内在特性使其容易受到降解在许多组织中存在的磷酸二酯酶，并且在恶性肿瘤中鉴定出较高的酶积累。此外，先前的研究表明，在肿瘤 - 居民抗原呈递中的刺激激活细胞（APC）是诱导肿瘤特异性CD8+T细胞免疫所必需的。我们最近开发了 CGAMP（LNP-sting）的APC靶向输送的新型纳米技术策略。我们组装LNP- 用磷脂酰丝氨酸在脂质体的外层上刺激，以促进其识别和摄取由APC和载荷CGAMP与磷酸钙复合以提高负载效率和将CGAMP释放到细胞质，并与刺伤结合。在这个项目中，我们建议建立一个最佳的LNP- 用于胸膜内给药的刺痛和测试是否会将免疫感染转化为促炎性热MPE。我们的中心假设是，胸膜内LNP丁字丁可以减轻免疫抑制MPE，从而为对抗PD-L1 ICB的有利反应奠定了基础。我们将测试 MPE小鼠模型和NSCLC患者的MPE样品的组合免疫疗法。我们建议建立一个最佳的LNP刺激性，用于胸膜内APC靶向刺痛激动剂的递送（AIM1）。然后我们会确定胸膜内LNP是否有效减轻免疫冷MPE（AIM2）。我们将最后确定是否胸膜内LNP丁字定丁字可提高ICB免疫疗法的效率（AIM3）。更重要的是，我们将获得洞察胸膜内LNP刺的生物学机制与抗PD-L1 ICB结合可能参与先天和适应性抗癌的免疫。这项工作很重要，因为它可能有一个可能影响MPE免疫疗法的潜力。