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

• 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
• 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

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 免疫耐受和激活之间的平衡是大多数病理的核心。免疫学 耐受性是指阻止针对非致病抗原的免疫激活的一系列过程。这个 与其他形式的免疫抑制相比，耐受性的关键区别在于它可以 仅抑制对特定抗原的反应性，而不会使宿主相对于 无关的病原体。免疫动态平衡依赖于对这一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或恶性肿瘤。到目前为止，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，虽然 免疫疗法代表着几十年来肿瘤学最大的范式转变，它们在很大程度上诱导了广泛的 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 病理学。在实体器官移植中，我们无法诱导完全的移植耐受，通常需要使用 终生免疫抑制药。因此，尽管对免疫耐受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治疗方法。 对多种疾病和临床环境的免疫耐受性。在这项建议中，我们寻求 开发一种将固有T细胞生物学与合成生物学相结合的新型模块化免疫疗法 基因组工程对宿主的内源性耐受程序进行再教育。我们假设，通过 激活或破坏异常耐受程序，我们可以治疗自身免疫性疾病和转移 癌症。淋巴结是外周耐受诱导的解剖中枢，这一特征被 恶性肿瘤在整个宿主转移的过程中。与传统的工程细胞疗法不同的是， 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的淋巴细胞， 我们提出的工程化细胞疗法是通过转移到淋巴结来改变其功能的 内源性耐受诱导导致自身免疫的解决或转移癌的治疗。至 为了实现这些目标，我们将开发一种T细胞疗法，通过将固有的 天真的T细胞归巢机制。在转移性癌症的背景下，我们将通过 包括嵌合抗原受体(CARS)，打破免疫耐受并在结扎时诱导激活 被贩卖到LNS的汽车的数量。在自身免疫的背景下，我们的治疗将诱导耐受性 在淋巴结中的抗原提呈细胞识别自身抗原提呈之后。因此，在 本项目结束后，我们将提供一种新的模块化免疫疗法，利用 以抗原特异的方式进行的内源性免疫反应。这种方法有可能提供 治疗患有衰弱的自身免疫和IV期癌症的患者，并很容易扩展到 移植、怀孕和传染病环境。