Delivery of cytokines for cancer immunotherapy using nanolayer-controlled trafficking of liposomal nanoparticles

使用纳米层控制的脂质体纳米颗粒运输输送用于癌症免疫治疗的细胞因子

基本信息

批准号：
10663293
负责人：
Paula T Hammond
金额：
$ 31.54万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663293
关键词：
Affect Anatomy Animal Model Binding Biodistribution Body Weight Cells Chemistry Clinical Coculture Techniques Confocal Microscopy Cytokine Receptor Binding Development Drug Controls Drug Delivery Systems Environment Enzyme-Linked Immunosorbent Assay Exclusion Flow Cytometry Formulation Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Harvest Health Human IL18 gene Immune Immune checkpoint inhibitor Immune response Immune system Immunotherapeutic agent Immunotherapy In Vitro Infiltration Inflammatory Interleukin-12 Interleukin-15 Interleukin-2 Intraperitoneal Injections Intravenous Investigation Kinetics Knowledge Lead Liposomes Lung Neoplasms Lymphocytic Infiltrate Malignant Neoplasms Malignant neoplasm of ovary Measures Membrane Memory Minority Modeling Monitor Mus Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Nucleic Acids Pathway interactions Patients Pharmaceutical Preparations Play Positioning Attribute Property Proteins Renaissance Role Serous Serum Solid Neoplasm Splenocyte Surface System Techniques Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Tumor Cell Line Tumor Tissue Work anti-PD1 therapy anti-tumor immune response biophysical properties cancer cell cancer immunotherapy cancer therapy cell type checkpoint inhibition cytokine design draining lymph node experience immune activation immunoregulation improved in vitro Assay in vitro testing in vivo in vivo evaluation intraperitoneal intravenous injection melanoma migration nano nanoparticle neoplastic cell ovarian neoplasm particle patient subsets programs rational design response spatiotemporal success synergism systemic toxicity therapy outcome tool trafficking tumor tumor microenvironment uptake

项目摘要

An immunosuppressive or immune excluded tumor microenvironment (TME) plays a key role in limiting the response of many tumor types to immunotherapy. One attractive strategy to accomplish increased lymphocyte infiltration in tumors is the use of cytokines, which can directly impact multiple immune pathways and reprogram the TME to enable a robust immune response against cancer cells. Unfortunately, despite this obvious potential, many cytokines have been limited clinically due to toxicity concerns. Rational drug delivery strategies that can rescue the therapeutic potential of cytokines could act as an important step in our ability to carefully manipulate the anti-tumor immune response in the TME and open the door for more effective immunotherapies. Nanoparticles (NPs) are a promising vehicle for the rescue of toxic cytokines. While many studies have used NPs to improve efficacy and toxicity, there remains a substantial knowledge gap surrounding the role of NP biophysical properties on enhanced delivery. There is much that is not yet understood about how nanoparticles traffic and how these differences can affect therapeutic outcomes. We are uniquely positioned to investigate the role of NP biophysical properties on cytokine delivery given our extensive experience in both NP design for targeted tumor cell delivery and in polyelectrolyte layer-by-layer (LbL) assembly. LbL-NP systems can be designed to modulate the release of multiple drugs from the core and from surrounding layers, often with time dependent staged release; whereas, manipulating the outer layer to possess certain surface chemistries and targeting moieties can significantly impact trafficking of particles on both the anatomical and cellular level. Using this system will allow for a systematic investigation of the role of these unique NP properties on effective cytokine delivery. The goal of this work is to understand and control the delivery of cytokines against solid tumors using LbL-NPs as a tool, with a focus on the impact of trafficking, localization and release kinetics of the particle and payload. Our work will focus on interleukin-12 (IL-12), one of the most potent and toxic proinflammatory cytokines for which we have recently demonstrated improved efficacy and lowered systemic toxicity by using LbL-NPs that bind to the surface membrane of ovarian cancer cells. Our studies will take place within the context of advanced serous ovarian cancer (OC), which has shown limited response to existing immunotherapies, and non-small cell lung cancers (NCSLC), which is highly responsive, but only for a defined subset of patients. IL-12 loaded NPs with external layers possessing a range of surface chemistries and targeting moieties will be examined for cellular and subcellular uptake and immune cell stimulation. Cytokine release kinetics will be examined and optimized, and nanoparticle systems will be examined in vivo for delivery of cytokines alone and in combination with anti- PD1 treatments in orthotopic syngeneic animal models. 1

免疫抑制或免疫排除的肿瘤微环境（TME）在限制限制许多肿瘤类型对免疫疗法的反应。实现增加淋巴细胞的一种有吸引力的策略肿瘤中的浸润是细胞因子的使用，它可以直接影响多个免疫途径并重新编程 TME能够对癌细胞产生强大的免疫反应。不幸的是，尽管有如此明显的潜力，由于毒性问题，许多细胞因子在临床上受到限制。合理的药物输送策略可以营救细胞因子的治疗潜力可能是我们仔细操纵能力的重要一步 TME中的抗肿瘤免疫反应，并为更有效的免疫疗法打开门。纳米颗粒（NP）是营救有毒细胞因子的有前途的载体。尽管许多研究都使用了 NP提高功效和毒性，围绕NP的作用仍然存在很大的知识差距增强输送的生物物理特性。关于纳米颗粒的方式尚未了解很多流量以及这些差异如何影响治疗结果。我们在调查鉴于我们在NP设计方面的丰富经验，NP生物物理特性在细胞因子递送中的作用靶向肿瘤细胞的递送和聚电解质分层（LBL）组装中。 LBL-NP系统可以是旨在调节从核心和周围层中释放多种药物的释放，通常会随着时间的推移依赖分期释放；鉴于，操纵外层以具有某些表面化学分配和靶向部分可以显着影响颗粒在解剖和细胞水平上的运输。使用该系统将允许系统研究这些独特的NP特性在有效细胞因子上的作用送货。这项工作的目的是了解和控制对实体瘤的细胞因子的递送使用LBL-NP作为工具，重点是贩运，本地化和释放动力学的影响粒子和有效载荷。我们的工作将集中于白介素12（IL-12），这是最有效和有毒的促炎细胞因子之一我们最近通过使用LBL-NPS来提高功效，并降低了全身毒性与卵巢癌细胞的表面膜结合。我们的研究将在高级的背景下进行浆液卵巢癌（OC），对现有免疫疗法的反应有限，非小细胞的反应有限肺癌（NCSLC）反应迅速，但仅适用于确定的患者子集。 IL-12加载的NP 将检查具有一系列表面化学和靶向部分的外层层的外层。和亚细胞摄取和免疫细胞刺激。将检查和优化细胞因子释放动力学将在体内检查纳米颗粒系统，以单独递送细胞因子并与抗原位同源动物模型中的PD1处理。 1