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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IL-1 β是在50多年前发现的，关于这些多效性细胞因子的知识已经有了很大的发展。从那时起呈指数级增长。这些分子的治疗用途受到毒性的限制，并且其阻断在炎性疾病中的成功有限。2017年，使用canukinumab的CANTOS试验和IL-1β的抗体，显示了阻断IL-1β和剂量依赖性降低IL-1β的意外关联。癌症的发病率，重新点燃了人们对IL-1分子在肿瘤免疫中的作用的兴趣。但我们的迄今为止的数据显示了未被重视的复杂性。我们和其他人已经证明，阻断IL-1β可以提高IL-1β的表达。小鼠癌症模型，以及我们发表的和初步的数据表明，肿瘤免疫的进化并不简单。例如，阻断IL-1β可以使免疫刺激性T细胞通过IL-1α激活以不受阻碍地进行，有利于肿瘤免疫。同时，阻断IL-1β对骨髓细胞独立地改变肿瘤微环境以有利于CD 8 T细胞介导的抗癌免疫力IL-1α的免疫治疗作用似乎是通过CD 8 T细胞IL-1 R1发挥作用的，并且我们认为，通过更全面地了解这一途径，我们可以大大增强其活性。此外，IL-1 R1对骨髓细胞的驱动作用似乎抑制了TME中的抗癌免疫，我们发现，假设了解这些影响将使我们能够精确地定位这一途径。可视化这些变化的组织病理学，我们采用了强大的CyCIF平台。检验假设在体内，我们将使用称为AcTakines的新型分子。这些化合物靶向细胞因子活性或阻断在体内精确地针对特定的细胞类型而没有全身毒性，这将有助于我们解剖这些免疫细胞。在肿瘤动物中的通路。因为这些药物正在开发用于未来的人类，我们的这项工作将作为更好地理解其未来在癌症免疫治疗中的应用的基础。我们相信这是一个新的和未探索的途径，通过它我们可以大大提高抗肿瘤免疫，为癌症的免疫治疗做出了重要贡献。