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.

项目概要/摘要免疫耐受和激活之间的平衡是大多数免疫学的核心。耐受性是指防止针对非致病性抗原的免疫激活的一组过程。与其他形式的免疫抑制相比，耐受性的关键区别特征是它的作用是仅抑制对特定抗原的反应，并且不会使宿主免疫抑制不相关的病原体的免疫稳态依赖于这种耐受激活轴的精确调节，以及迄今为止，几乎所有的治疗方法都会导致这种平衡的破坏。自身免疫性疾病会导致某种形式的非特异性免疫抑制，而离线。免疫疗法代表了肿瘤学几十年来最大的范式转变，它们在很大程度上起到了诱导广泛的作用以非特异性方式激活免疫，通常会导致不良事件，包括自身免疫在实体器官移植中，我们通常无法诱导完全的移植物耐受。因此，尽管对免疫耐受性进行了半个多世纪的研究，仍然迫切需要开发能够控制抗原特异性的疗法在本提案中，我们寻求对多种疾病和临床环境的免疫耐受。开发一类新型模块化免疫疗法，将内在 T 细胞生物学与合成生物学相结合，基因组工程来重新教育宿主的内源性耐受程序。激活或破坏异常的耐受程序，我们可以治疗自身免疫性疾病和转移性疾病淋巴结是外周耐受诱导的解剖中心，这是癌症所具有的特征。与传统的工程细胞疗法不同，它们在整个宿主中转移。作用机制依赖于致病细胞的细胞溶解，包括肿瘤或自身反应性淋巴细胞，我们建议的工程细胞疗法通过运输到淋巴结来改变功能内源性耐受诱导导致自身免疫的解决或转移性癌症的治疗。为了实现这些目标，我们将开发一种 T 细胞疗法，通过利用内在的特性来专门定位淋巴结。在转移性癌症的背景下，我们将通过以下方法来增强这种方法：包含嵌合抗原受体 (CAR)，可破坏免疫耐受并在连接后诱导激活在自身免疫的背景下，我们的疗法将诱导耐受性。因此，在淋巴结中的抗原呈递细胞识别自身抗原呈递之后。该项目结束后，我们将提供一类新型模块化免疫疗法，该疗法利用这种方法有可能以抗原特异性的方式产生内源性免疫反应。治愈患有自身免疫衰弱和 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。