Using the IL-1R1 and its ligands to optimize the T cell immune response to cancer

使用 IL-1R1 及其配体优化 T 细胞对癌症的免疫反应

基本信息

批准号：
10801033
负责人：
THOMAS S. KUPPER
金额：
$ 61.87万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10801033
关键词：
Address Animals Antibodies Blocking Antibodies CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cells Chronic Clinical Trials Combined Modality Therapy Data Dendritic Cells Development Disease Dose Eye Future Gene Expression Gene Expression Profile Goals Heterozygote Human IL1R1 gene Immune Immune checkpoint inhibitor Immune response Immunologic Stimulation Immunosuppression Immunotherapeutic agent Incidence Infiltration Inflammatory Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Knowledge Ligands Macrophage Malignant Neoplasms Malignant neoplasm of lung Mediating Memory Mus Myelogenous Myeloid Cell Activation Myeloid Cells Pathway interactions Patients Pharmaceutical Preparations Phenotype Process Production Publishing Receptor Signaling Role Signal Transduction System T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Intervention Therapeutic Uses Time Tissues Toxic effect Tumor Immunity Tumor Promotion Visualization Work anakinra anti-PD1 antibodies anti-cancer antibody inhibitor autocrine cancer immunotherapy cancer therapy cell type cytokine design immune cell infiltrate improved in vivo interest mouse model neutrophil novel novel therapeutics paracrine programmed cell death protein 1 programs promoter success synergism systemic toxicity therapeutic candidate trafficking tumor tumor growth tumor microenvironment

项目摘要

IL-1α and β were discovered more than 50 years ago, and knowledge about these pleiotropic cytokines has grown exponentially since that time. Therapeutic use of these molecules has been limited by toxicity, and their blockade has had limited success in inflammatory disorders. In 2017, the CANTOS trial using canukinumab and antibody to IL-1β, showed an unexpected association of blocking IL-1β and a dose dependant reduction in the incidence of cancers, rekindling interest in the role of IL-1’s molecules in tumor immunity. However, our data thus far suggests unappreciated complexity. We and others have shown that the of blocking IL-1β in mouse models of cancer, and our published and preliminary data suggest that the mechanism by which anti- tumor immunity evolves is not straightforward. For example, blocking IL-1β permits immunostimulatory T cell activation by IL-1α to proceed unopposed, favoring tumor immunity. In parallel, blocking IL-1β’s effects on myeloid cells modifies the tumor microenvironment independently to favor CD8 T cell mediated anti-cancer immunity. The immunotherapeutic effects of IL-1α appear to be operating through the CD8 T cell IL-1R1, and we propose that by understanding this pathway more completely, we can greatly enhance its activity. Moreover, IL-1R1-driven effects on myeloid cells appear to inhibit anti-cancer immunity in the TME, and we hypothesize that understanding these effects will allow us to target this pathway with precision. To visualize these changes histopathologically, we have employed the powerful CyCIF platform. To test hypotheses in vivo, we will use novel molecules known as AcTakines. These compounds target cytokine activity or blockade precisely to specific cell types in vivo without systemic toxicity and will help us to dissect these immune pathways in tumor-bearing animals. Because these drugs are being developed for future use in humans, our work will serve as a basis for a better mechanistic understanding of their future use in cancer immunotherapy. We believe this is a new and unexplored pathway through which we can greatly enhance anti-tumor immunity, contributing fundamentally to immunotherapy of cancer.

IL-1α 和 β 已于 50 多年前被发现，并且对这些多效性细胞因子的了解已经深入人心从那时起，这些分子的治疗用途一直受到毒性和它们的限制。 2017 年，使用 canukinumab 进行的 CANTOS 试验在炎症性疾病方面的封锁取得了有限的成功。和 IL-1β 抗体，显示出阻断 IL-1β 和剂量依赖性减少的意外关联。癌症的发病率，重新燃起了人们对 IL-1 分子在肿瘤免疫中的作用的兴趣。迄今为止的数据表明，我们和其他人已经表明，阻断 IL-1β 的复杂性尚未得到重视。癌症小鼠模型，以及我们发表的初步数据表明，抗- 肿瘤免疫的进化并不简单，例如，阻断 IL-1β 可以产生免疫刺激性 T 细胞。 IL-1α 的激活不受阻碍地进行，有利于肿瘤免疫，同时阻断 IL-1β 对肿瘤免疫的影响。骨髓细胞独立地改变肿瘤微环境以支持 CD8 T 细胞介导的抗癌作用 IL-1α 的免疫治疗作用似乎是通过 CD8 T 细胞 IL-1R1 发挥作用的。我们建议，通过更全面地了解该途径，我们可以大大增强其活性。此外，IL-1R1 对骨髓细胞的驱动作用似乎会抑制 TME 中的抗癌免疫，我们此外，了解这些影响将使我们能够精确地瞄准这一途径。这些组织病理学变化，我们采用了强大的 CyCIF 平台来检验假设。在体内，我们将使用称为 AcTakines 的新型分子，这些目标化合物可阻断细胞因子活性。精确地针对体内特定的细胞类型，而没有全身毒性，这将有助于我们剖析这些免疫细胞因为这些药物正在开发用于未来在人类中的使用。这项工作将为更好地理解其未来在癌症免疫治疗中的应用奠定基础。我们相信这是一条新的、未经探索的途径，通过它我们可以大大增强抗肿瘤免疫力，为癌症的免疫治疗做出了根本性的贡献。