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: 10058872
• 负责人: Efstathios Karathanasis
• 金额: $ 59.1万
• 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/10058872
• 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.

项目摘要 一线化疗是三阴性乳腺癌（TNBC）患者的护理标准。尽管 短期反应是可以实现的，大多数患者因转移而屈服于复发。微量表 包含一小部分休眠传播肿瘤细胞（DDTC），这些肿瘤细胞（DDTC）在 静态/感觉状态在启动其“爆炸性”转移性产物之前。标准化疗是 完全无效地抵抗速度较慢的DDTC。相反，癌症免疫疗法基于 免疫识别和靶向杀死肿瘤细胞的前提，因此具有控制的承诺能力 休眠转移性癌细胞。但是，免疫疗法的一个主要障碍是克服深刻的 肿瘤微环境（TME）内的免疫抑制。 TME与 功能失调的抗原呈递细胞（APC）。改变TME的一种有效方法是对这些 抑制性APC适当激活刺激肿瘤抗原特异性T细胞的APC。我们设计了一个 免疫刺激性纳米颗粒利用转移性TME的独特生理特征， 允许全身传递纳米颗粒在TME内实现强大的免疫刺激。首先，到 驱动可持续的抗肿瘤免疫响应，我们通过共同利用两种协同的先天免疫途径 提供两名免疫控制器。免疫NP与干扰素的刺激剂共同加载 基因（STING）途径和Toll样受体4（TLR4）激动剂，它们协同产生高水平 I型干扰素（IFN）β。双动振动者NP保证通过同一APC吸收两种激动剂， 引起功能协同作用。其次，免疫NP的收藏夹熟练地呈现了每种激动剂 APC的适当细胞内位置。第三，免疫NP专为全身管理设计 靶向富含APC的转移的周围区域，主要导致APC细胞摄取。作为 结果，肿瘤部位内产生的高水平的IFNβ导致APC和NK细胞的激活 因此，推动了其他免疫细胞的募集以及肿瘤反应的激活 细胞毒性CD8+ T细胞。任何免疫NP相关的毒性都是最小且可逆的。我们的中心 假设是，针对的免疫NP的双动货物（STING和TLR4激动剂） 转移的血管周区域将产生强大的IFNβ驱动的抗肿瘤免疫响应。 AIM 1：优化一种以高效率为目标的免疫NP设计，该设计针对转移性TME，并共同培养。 以最佳功能协同作用的刺激/TLR4激动剂比以双动货物的递送。 目标2：评估免疫NP的短期和长期安全性，并表征 与剂量和免疫NP给药频率相关的抗肿瘤免疫复杂。 AIM 3：评估免疫NP的治疗效率作为单一疗法，并与免疫结合使用 转移性TNBC鼠模型中的检查点抑制剂。