A modular cell therapy platform for controlling immunological tolerance

用于控制免疫耐受的模块化细胞治疗平台

基本信息

批准号：
10725007
负责人：
Nathan Edward Reticker-Flynn
金额：
$ 47.37万
依托单位：
STANFORD UNIVERSITY
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：
2023-08-04 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725007
关键词：
Adaptive Immune System Adjuvant Adverse event Anatomy Antigen Presentation Antigen-Presenting Cells Antigens Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Benign Cell Therapy Cells Cellular biology Chronic Clinical Clonal Anergy Clonal Deletion Communicable Diseases Cytolysis Dendritic Cells Disease Disseminated Malignant Neoplasm Education Endowment Engineering Equilibrium Generations Genome engineering Goals Graft Tolerance Heart Home Homeostasis Homing Immune Immune System Diseases Immune Tolerance Immune checkpoint inhibitor Immune response Immunocompromised Host Immunologic Adjuvants Immunologic Memory Immunosuppression Immunosuppressive Agents Immunotherapy Ligation Lymphocyte Maintenance Malignant Neoplasms Molecular Neoplasm Metastasis Oncology Organ Transplantation Pathogenicity Pathology Patients Peripheral Persons Pharmaceutical Preparations Pregnancy Prevention Process Production RNA Interference Reactive Inhibition Regulatory T-Lymphocyte Research Resistance Resolution Site Solid Steroids T cell therapy T-Lymphocyte Therapeutic Thymus Gland Tissues Transplantation Transplantation Tolerance Tuberculosis Tumor Immunity United States adaptive immune response anti-tumor immune response autoreactivity cancer immunotherapy central tolerance chimeric antigen receptor cytokine engineered T cells fetal fighting immune activation immune-related adverse events lymph nodes novel pathogen peripheral tolerance post-doctoral training prevent programs response reverse tolerance secondary lymphoid organ synthetic biology therapy development tool trafficking tumor

项目摘要

Project Summary/Abstract The balance between immune tolerance and activation lies at the heart of most pathologies. Immunological tolerance refers to the set of processes that prevent immune activation against non-pathogenic antigens. The key distinguishing feature of tolerance compared to other forms of immunosuppression is that it operates to inhibit reactivity only to specific antigens and does not render the host immunosuppressed with respect to unrelated pathogens. Immune homeostasis relies upon precise tuning of this tolerance-activation axis, and disruption of this balance results in autoimmunity or malignancy. To date, nearly all our treatments for autoimmune disease result in some form of nonspecific immunosuppression. Conversely, while immunotherapies represent the greatest paradigm shift in oncology in decades, they largely act to induce broad immune activation in a nonspecific manner that often results in adverse events, including autoimmune pathologies. In solid organ transplantation, our inability to induce complete graft tolerance often requires the use of lifelong immunosuppressants. Thus, despite over a half-century of research into immunological tolerance, there remains a pressing need to develop therapies capable of controlling antigen-specific immunological tolerance for a wide range of diseases and clinical settings. In this proposal, we seek to develop a new class of modular immunotherapies that couple intrinsic T cell biology with synthetic biology and genome engineering to reeducate endogenous tolerance programs in the host. We hypothesize that by activating or disrupting aberrant tolerance programs, we can treat autoimmune disease and metastatic cancer. Lymph nodes are the anatomical hubs of peripheral tolerance induction, a feature that is coopted by malignancies as they metastasize throughout the host. Unlike conventional engineered cell therapies whose mechanism of action relies upon cytolysis of pathogenic cells, including tumors or autoreactive lymphocytes, the engineered cell therapies that we propose instead function by trafficking to lymph nodes to alter endogenous tolerance induction resulting in resolution of autoimmunity or treatment of metastatic cancer. To achieve these goals, we will develop a T cell therapy that specifically homes to lymph nodes by coopting intrinsic naïve T cell homing machinery. In the context of metastatic cancer, we will augment this approach with the inclusion of chimeric antigen receptors (CARs) that break immune tolerance and induce activation upon ligation of the CARs following trafficking to LNs. In the context of autoimmunity, our therapies will induce tolerance following recognition of autoantigen presentation by antigen presenting cells in lymph nodes. Thus, at the conclusion of this project, we will deliver a new class of modular immunotherapies that harnesses the endogenous immune response in an antigen-specific manner. This approach has the potential to deliver cures to patients suffering from debilitating autoimmunity and stage IV cancer and is readily extensible to transplantation, pregnancy, and infectious disease settings.

项目摘要/摘要免疫耐受性和激活之间的平衡在于大多数病理的核心。免疫学公差是指防止免疫激活非致病抗原的过程。与其他形式的免疫抑制相比，公差的关键区别特征是它起作用仅抑制对特定抗原的反应性，并且不会使宿主相对于无关病原体。免疫稳态依赖于这种耐受激活轴的精确调整，并且这种平衡的破坏会导致自身免疫性或恶性肿瘤。迄今为止，我们几乎所有的治疗方法自身免疫性疾病会导致某种形式的非特异性免疫抑制。相反，而免疫疗法代表了数十年来肿瘤学上最大的范式转变，它们在很大程度上诱导了广泛的作用以非特异性方式进行免疫激活，通常会导致预先事件，包括自身免疫病理。在固体器官移植中，我们无法诱导完全的移植耐受性通常需要使用终身免疫抑制剂。这是超过半个世纪的免疫耐受性研究，仍然需要开发能够控制抗原特异性的疗法的迫切需求各种疾病和临床环境的免疫耐受性。在此提案中，我们寻求开发一类新的模块化免疫疗法，将固有的T细胞生物学与合成生物学和基因组工程，以重新教育宿主中的内源性耐受性计划。我们通过激活或破坏异常容忍计划，我们可以治疗自身免疫性疾病和转移性疾病癌症。淋巴结是周围耐受性诱导的解剖枢纽，该特征由 Malignancys在整个主持人中转移。与传统的工程细胞疗法不同作用机理依赖于致病细胞的细胞解析，包括肿瘤或自身反应性淋巴细胞，我们建议通过运输到淋巴结来改变的工程细胞疗法内源性耐受性诱导导致自身免疫性或转移性癌症治疗。到实现这些目标，我们将开发一种T细胞疗法，该疗法专门用于淋巴结，通过固有的幼稚的T细胞归巢机械。在转移性癌症的背景下，我们将通过嵌入嵌合抗原受体（CAR），这些抗原受体（CAR）破坏免疫耐受性并在连接时诱导激活贩运LNS后的汽车。在自身免疫的背景下，我们的疗法将引起宽容在识别抗原呈现淋巴结中细胞自身抗原的表现之后。那在结论该项目，我们将提供一类新的模块化免疫疗法，以利用内源性免疫反应以抗原特异性方式。这种方法有可能交付治疗患有虚弱的自身免疫性和IV期癌症的患者，并且很容易扩展到移植，怀孕和传染病环境。