T-cell monitoring and immunotherapy for treating graft-versus-host disease

用于治疗移植物抗宿主病的 T 细胞监测和免疫治疗

• 批准号: 8700612
• 负责人: EVERETT MEYER
• 金额: $ 13.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700612
• 关键词: Acute Graft Versus Host Disease; Affect; Antigen Targeting; Antigens; Area; Base Sequence; Bioinformatics; Biometry; Blood; Bone Marrow Transplantation; Cells; Clinic; Clinical; Clinical Research; Collaborations; Complication; Data; Development; Diagnosis; Disease; Flow Cytometry; Future; Genomics; Goals; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Human; IL2RA gene; Immune; Immune System Diseases; Immune system; Immunologic Monitoring; Immunosuppressive Agents; Immunotherapy; Interleukin-2; Knowledge; MHC Interaction; Measures; Mentors; Mentorship; Minor; Modeling; Monitor; Morbidity - disease rate; Mus; Outcome; Patients; Phenotype; Physicians; Pre-Clinical Model; Prevention; Publishing; Refractory; Refractory Disease; Regulatory T-Lymphocyte; Research; Research Design; Risk; Scientist; Steroids; T cell therapy; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Training; Translating; Work; Yeasts; base; clinical decision-making; clinical practice; clinically relevant; graft vs host disease; hematopoietic cell transplantation; improved; isoimmunity; mortality; mouse model; multidisciplinary; new technology; novel; novel strategies; prevent; public health relevance; response; treatment response

Abstract Hematopoietic cell transplantation (HCT) is a potentially curative therapy for a broad range of hematological malignancies and other disorders, however, acute GVHD is a major complication that limits the use and results in significant morbidity and mortality.1-3 About half of patients with acute GVHD will have steroid refractory disease that carries an especially high mortality with few treatment options. Because there are currently no clinical tests to prospectively identify or treat steroid refractory GVHD, therapy is largely empiric.2 My central long-term goal is to combine the use and development of T cell immune monitoring and T cell based immunotherapy to improve outcomes for HCT patients and, eventually, many other patients. In this application, we propose work that could redefine how we understand, diagnose and treat GVHD with implications for many other immunologic diseases. We propose to apply cutting-edge nucleotide sequencing- based approaches to identify and track T cells causing GVHD. We propose to show that this knowledge can be used to guide the development and implementation of improved monitoring and new therapies to treat these patients. This includes the development of immunosuppressive Tregulatory cells to treat GVHD We propose to study pre-clinical models of GVHD and to test if novel 'educated' donor CD25+ Tregs that appear to treat active and severe GVHD might be translated to the clinic. This will be accomplished if the phenotype of eTregs is clarified and we have answered the question as to whether or not these cells impair graft-versus tumor response and function in clinically relevant settings. We anticipate that eTregs will require MHC interactions to be generated, depend less upon IL-2 to function and will prevent the expansion of GVHD- associated T cell clones identified by T cell repertoire sequencing and/or response to known GVHD antigens. We propose also to defining T cell signatures that predict, confirm or stratify acute GVHD in patients. We propose to integrate flow cytometry and single cell genomics into this approach, advances that could finally allow clinicians to accession the function of the adaptive immune system in making clinical decisions. We will accomplish the goals of our study if we confirm TCR sequencing can be used to risk stratify steroid refractory patients or extended to help predict GVHD. In addition, the aim will be accomplished if we can identify the phenotype and treatment response of T cells highly implicated in GVHD, both for patients undergoing conventional HCT and for those receiving Tregs for the prevention or treatment of GVHD. As an extension of this work, we have conceived of novel approaches to identify GVHD target antigens by integrating high- throughput TCR sequencing for GVHD target antigen discovery. This proposal will allow scientists and clinical practitioners to better understand and control alloimmunity and hopefully help to prevent or cure GVHD.

抽象的 造血细胞移植（HCT）是一种潜在的治疗多种血液病的方法 然而，对于恶性肿瘤和其他疾病，急性 GVHD 是限制其使用和结果的主要并发症 发病率和死亡率显着。1-3 大约一半的急性 GVHD 患者对类固醇无效 死亡率特别高且治疗选择很少的疾病。因为目前没有 前瞻性识别或治疗类固醇难治性 GVHD 的临床试验，治疗主要是经验性的。2 我的中心 长期目标是将T细胞免疫监测和基于T细胞的应用和开发结合起来 免疫疗法可改善 HCT 患者的预后，并最终改善许多其他患者的预后。 在此应用中，我们提出的工作可以重新定义我们如何理解、诊断和治疗 GVHD 对许多其他免疫疾病的影响。我们建议应用尖端的核苷酸测序- 基于方法来识别和跟踪引起 GVHD 的 T 细胞。我们建议证明这些知识可以 用于指导改进监测和治疗这些疾病的新疗法的开发和实施 患者。这包括开发免疫抑制性调节细胞来治疗 GVHD 我们建议研究 GVHD 的临床前模型，并测试新型“受过教育”的供体 CD25+ Tregs 是否能够 似乎治疗活动性和严重 GVHD 可能会转化为临床。如果 eTregs 的表型已阐明，并且我们已经回答了这些细胞是否损害的问题 临床相关环境中的移植物抗肿瘤反应和功能。我们预计 eTreg 将需要 MHC 相互作用产生，较少依赖 IL-2 发挥作用，并且会阻止 GVHD-的扩展 通过 T 细胞库测序和/或对已知 GVHD 抗原的反应来鉴定相关的 T 细胞克隆。 我们还建议定义预测、确认或分层患者急性 GVHD 的 T 细胞特征。我们 建议将流式细胞术和单细胞基因组学整合到这种方法中，这些进展最终可以 允许临床医生在做出临床决策时加入适应性免疫系统的功能。我们将 如果我们确认 TCR 测序可用于对类固醇难治性进行风险分层，就可以实现我们的研究目标 患者或扩展以帮助预测 GVHD。此外，如果我们能够确定 T 细胞的表型和治疗反应与 GVHD 高度相关，均适用于接受 GVHD 治疗的患者 传统 HCT 以及接受 Tregs 预防或治疗 GVHD 的患者。作为延伸 在这项工作中，我们构想出了通过整合高水平抗原来识别 GVHD 靶抗原的新方法。 用于 GVHD 靶抗原发现的高通量 TCR 测序。 该提案将使科学家和临床实践者更好地理解和控制同种免疫和 希望有助于预防或治疗 GVHD。