A modular cell therapy platform for controlling immunological tolerance

项目总结/摘要 免疫耐受和激活之间的平衡是大多数病理学的核心。免疫 耐受性是指阻止针对非病原性抗原的免疫激活的一组过程。的 与其他形式的免疫抑制相比，耐受性的关键区别特征在于， 仅抑制对特异性抗原的反应性，并且不会使宿主在以下方面受到免疫抑制： 无关的病原体。免疫稳态依赖于对耐受-激活轴的精确调节， 这种平衡的破坏导致自身免疫或恶性肿瘤。到目前为止，几乎所有的治疗方法， 自身免疫性疾病导致某种形式非特异性免疫抑制。尽管可 免疫疗法代表了几十年来肿瘤学中最大的范式转变，它们在很大程度上诱导广泛的免疫应答。 以非特异性方式的免疫激活，经常导致不良事件，包括自身免疫性 病理学在实体器官移植中，我们无法诱导完全移植物耐受，通常需要使用 终身免疫抑制剂。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 免疫耐受性用于广泛的疾病和临床环境。在本建议中，我们力求 开发一类新的模块化免疫疗法，将内在T细胞生物学与合成生物学结合起来， 基因组工程，以再教育宿主的内源性耐受程序。我们假设 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性疾病， 癌淋巴结是外周耐受诱导的解剖学枢纽，这一特征是由 恶性肿瘤，因为他们转移到整个主机。与传统的工程细胞疗法不同， 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， 我们提出的工程细胞疗法，而是通过运输到淋巴结， 内源性耐受诱导导致自身免疫消退或转移性癌症的治疗。到 为了实现这些目标，我们将开发一种T细胞疗法，通过选择内源性T细胞， 幼稚T细胞归巢机制。在转移性癌症的背景下，我们将增加这种方法， 包含嵌合抗原受体（汽车），其破坏免疫耐受并在连接时诱导活化 贩运到土著民族之后的汽车数量。在自身免疫的背景下，我们的疗法将诱导耐受性 在淋巴结中抗原呈递细胞识别自身抗原呈递后。因此，在 该项目的结论，我们将提供一类新的模块化免疫疗法，利用 内源性免疫应答以抗原特异性的方式。这种方法有可能实现 治疗患有使人衰弱的自身免疫和IV期癌症的患者，并且容易扩展到 移植、妊娠和传染病环境。

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.