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

• 批准号: 10430179
• 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
• 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/10430179
• 关键词: Affect; Anatomy; Animal Model; Binding; Biodistribution; Body Weight; Cells; Chemistry; Clinical; Coculture Techniques; Confocal Microscopy; Cytokine Receptors; Development; Drug Controls; Drug Delivery Systems; Environment; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Formulation; Goals; Growth; Harvest; Health; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Inflammatory; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-2; Intraperitoneal Injections; Intravenous; Investigation; Kinetics; Knowledge; Lead; Liposomes; Lung Neoplasms; Lymphocyte; 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; Ursidae Family; 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; nanoparticle; neoplastic cell; ovarian neoplasm; particle; patient subsets; rational design; response; spatiotemporal; success; synergism; systemic toxicity; therapy outcome; tool; trafficking; tumor; tumor microenvironment; uptake

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）在限制肿瘤微环境（TME）方面发挥着关键作用。 许多肿瘤类型对免疫治疗的反应。一种增加淋巴细胞的有吸引力的策略 肿瘤浸润是利用细胞因子，它可以直接影响多种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，尽管有这种明显的潜力， 由于毒性问题，许多细胞因子在临床上受到限制。合理的给药策略可以 拯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，为更有效的免疫疗法打开了大门。 纳米颗粒（NP）是拯救有毒细胞因子的有前途的载体。虽然许多研究已经使用 NP 可以改善功效和毒性，但围绕 NP 的作用仍存在很大的知识差距 增强递送的生物物理特性。关于纳米颗粒如何发挥作用，目前还有很多问题尚不清楚 交通以及这些差异如何影响治疗结果。我们处于独特的地位来调查 鉴于我们在 NP 设计方面的丰富经验，NP 生物物理特性对细胞因子传递的作用 靶向肿瘤细胞递送和聚电解质逐层（LbL）组装。 LbL-NP 系统可以 旨在调节多种药物从核心和周围层的释放，通常随着时间的推移 相关分阶段发布；然而，操纵外层以拥有某些表面化学性质和 靶向部分可以在解剖学和细胞水平上显着影响颗粒的运输。使用 该系统将允许系统研究这些独特的 NP 特性对有效细胞因子的作用 送货。这项工作的目标是了解和控制针对实体瘤的细胞因子的传递 使用 LbL-NPs 作为工具，重点关注 LbL-NPs 的贩运、定位和释放动力学的影响 粒子和有效载荷。 我们的工作重点是白细胞介素 12 (IL-12)，它是最有效、最具毒性的促炎细胞因子之一。 我们最近证明，通过使用 LbL-NP 可提高疗效并降低全身毒性 与卵巢癌细胞的表面膜结合。我们的研究将在先进的背景下进行 浆液性卵巢癌（OC），对现有免疫疗法的反应有限，以及非小细胞癌 肺癌（NCSLC），其反应性很高，但仅针对特定的患者亚群。负载 IL-12 的 NP 具有一系列表面化学和靶向部分的外层将被检查细胞 以及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， 纳米颗粒系统将在体内进行单独和与抗-细胞因子组合的细胞因子递送检查 原位同基因动物模型中的 PD1 治疗。 1