Targeted immuno-nanoparticles for directing antitumor immune response against breast cancer metastasis

靶向免疫纳米颗粒用于指导针对乳腺癌转移的抗肿瘤免疫反应

• 批准号: 10225633
• 负责人: Efstathios Karathanasis
• 金额: $ 59.11万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10225633
• 关键词: Agonist; Antigen Targeting; Antigen-Presenting Cells; Area; Binding; Breast cancer metastasis; CD8-Positive T-Lymphocytes; Cancer Biology; Cells; Clinical; Clinics and Hospitals; Comprehensive Cancer Center; Cytosol; Cytotoxic T-Lymphocytes; Cytotoxic agent; Deposition; Disease; Disseminated Malignant Neoplasm; Endosomes; Exhibits; Frequencies; Immune; Immune checkpoint inhibitor; Immunization; Immunomodulators; Immunooncology; Immunosuppression; Immunotherapy; Interferon Type I; Interferon-beta; Lead; Lilium; Lipid A; Lipids; Location; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Micrometastasis; Nanotechnology; Natural Killer Cells; Neoplasm Metastasis; Pathway interactions; Patient Care; Patients; Periodicity; Physiological; Population; Porifera; Production; Protons; Publishing; Recurrence; Research Personnel; Route; Safety; Silicon Dioxide; Site; Stimulator of Interferon Genes; Stimulus; Surface; TLR4 gene; Testing; Toxic effect; Treatment Efficacy; Tumor Antigens; Universities; University Hospitals; anti-tumor immune response; antigen-specific T cells; base; cancer cell; cancer immunotherapy; chemotherapy; cytotoxic CD8 T cells; design; dosage; immunoregulation; innate immune pathways; lipophilicity; mouse model; nanoparticle; nanoparticle delivery; neoplasm immunotherapy; neoplastic cell; recruit; response; senescence; standard of care; synergism; triple-negative invasive breast carcinoma; tumor; tumor immunology; tumor microenvironment; uptake

PROJECT SUMMARY First-line chemotherapy is the standard of care for patients with triple-negative breast cancer (TNBC). While short-term response is achievable, most patients succumb to recurrence due to metastasis. Micrometastasis encompasses a small population of dormant disseminated tumor cells (dDTCs) that survive in quiescent/senescent states prior to initiating their ‘explosive’ metastatic outgrowth. Standard chemotherapy is completely ineffective against the slow-dividing dDTCs. In contrast, cancer immunotherapy is based on the premise of immune-recognition and targeted killing of tumor cells, thus possess the promising power to control dormant metastatic cancer cells. However, one major hurdle in immunotherapy is to overcome the profound immunosuppression within the tumor microenvironment (TME). TME is associated with the accumulation of dysfunctional antigen-presenting cells (APCs). An effective approach to alter TME is to reprogram these inhibitory APCs into properly activated APCs that stimulate tumor antigen-specific T cells. We designed an immuno-stimulatory nanoparticle that exploits the unique physiological features of metastatic TME, which allows the systemic delivery of nanoparticles to achieve a robust immunostimulation within the TME. First, to drive a sustainable antitumor immune response, we harness two synergistic innate immune pathways by co- delivering two immune agonists. The immuno-NP is co-loaded with an agonist of the Stimulator of Interferon Genes (STING) pathway and a Toll-like receptor 4 (TLR4) agonist, which synergize to produce high levels of Type I interferon (IFN) β. The dual-agonist NP guarantees uptake of both agonists by the same APC, which elicits functional synergy. Second, the immuno-NP facilitates proficient presentation of each agonist to the appropriate intracellular location of APCs. Third, the immuno-NP is designed for systemic administration targeting the APC-rich perivascular areas of metastasis, leading to uptake predominantly by APC cells. As a result, high levels of IFNβ produced within the tumor site lead to the activation of APC and NK cells that consequently drive the recruitment of additional immune cells as well as the activation of tumor-reactive cytotoxic CD8+ T cells. Any immuno-NP-associated toxicity was minimal and reversible. Our central hypothesis is that the dual-agonist cargo (STING and TLR4 agonists) of the immuno-NP targeted to the perivascular regions of metastasis will produce a strong IFNβ-driven antitumor immune response. Aim 1: Optimize an immuno-NP design that targets the metastatic TME with high efficiency and mediates co- delivery of the dual-agonist cargo at the ratio of STING/TLR4 agonists for optimal functional synergy. Aim 2: Evaluate the short and long-term safety profile of the immuno-NP and characterize the mechanism of antitumor immune responses associated with dosage and frequency of immuno-NP administration. Aim 3: Evaluate the therapeutic efficacy of the immuno-NP as a monotherapy and in combination with immune checkpoint inhibitors in murine models of metastatic TNBC.

项目概要 一线化疗是三阴性乳腺癌 (TNBC) 患者的标准治疗方法。尽管 短期缓解是可以实现的，大多数患者因转移而复发。微转移 包含一小群休眠播散性肿瘤细胞 (dDTC)，它们存活于 在开始“爆炸性”转移生长之前的静止/衰老状态。标准化疗是 对缓慢分裂的 dDTC 完全无效。相比之下，癌症免疫疗法基于 以免疫识别和靶向杀伤肿瘤细胞为前提，具有良好的控制能力 休眠的转移癌细胞。然而，免疫疗法的一个主要障碍是克服深刻的问题 肿瘤微环境（TME）内的免疫抑制。 TME 与积累有关 功能失调的抗原呈递细胞（APC）。改变 TME 的一个有效方法是重新编程这些 抑制性 APC 转化为适当激活的 APC，刺激肿瘤抗原特异性 T 细胞。我们设计了一个 免疫刺激纳米颗粒利用了转移性 TME 的独特生理特征， 允许全身输送纳米粒子，以在 TME 内实现强大的免疫刺激。首先，要 为了驱动可持续的抗肿瘤免疫反应，我们通过共同利用两种协同的先天免疫途径 递送两种免疫激动剂。免疫纳米粒子与干扰素刺激剂的激动剂共同负载 基因 (STING) 通路和 Toll 样受体 4 (TLR4) 激动剂，协同作用产生高水平的 I 型干扰素 (IFN) β。双激动剂 NP 保证同一个 APC 摄取两种激动剂，这 引发功能协同作用。其次，免疫 NP 有助于将每种激动剂熟练地呈递给 APC 的适当细胞内位置。第三，immuno-NP被设计用于全身给药 靶向富含 APC 的血管周围转移区域，导致主要被 APC 细胞摄取。作为一个 结果，肿瘤部位产生高水平的 IFNβ 导致 APC 和 NK 细胞激活， 因此促进额外免疫细胞的招募以及肿瘤反应性细胞的激活 细胞毒性 CD8+ T 细胞。任何与免疫 NP 相关的毒性都很小并且是可逆的。我们的中央 假设是免疫 NP 的双激动剂货物（STING 和 TLR4 激动剂）靶向 血管周围转移区域将产生强烈的 IFNβ 驱动的抗肿瘤免疫反应。 目标 1：优化免疫 NP 设计，高效靶向转移性 TME 并介导协同作用 以 STING/TLR4 激动剂的比例递送双激动剂货物，以获得最佳的功能协同作用。 目标 2：评估免疫 NP 的短期和长期安全性并表征其机制 抗肿瘤免疫反应与免疫NP给药的剂量和频率相关。 目标 3：评估免疫 NP 作为单一疗法以及与免疫联合疗法的治疗效果 转移性 TNBC 小鼠模型中的检查点抑制剂。