Identification of circulating and tissue-specific autoimmune responses in checkpoint inhibitor-induced immune-related adverse events

项目摘要/摘要 此重新提交申请的目标是培训David Y.oh医学博士，他是一名内科肿瘤学家和 免疫学家，为他提供了成为一名独立资助的实验室研究人员的技能 检查点抑制剂(CPIs)后的免疫相关不良事件(IRAE)。消费物价指数是癌症的免疫疗法 激活抗肿瘤免疫反应，从而提高几种癌症的存活率，但也会引发 IRAE是对正常组织的自身免疫反应，代表着发病率的增加来源 为癌症患者准备的。拟议的培训计划结合了教学和实践经验，以提供 基金会在以下领域与他现有的专业知识相辅相成，对实现他的 研究目标：(1)基础B细胞生物学，包括B细胞驱动的自身免疫和自身抗体的方法 发现和验证，(2)下一代测序方法和分析，包括单细胞方法 (3)临床试验设计方法，包括生物统计学方法和相关方法 科学。该研究计划通过研究来解决我们对IRAE机制理解上的主要局限。 在IRAEs中，细胞(T细胞)和体液(B细胞)对自身抗原都有反应。通过研究伊拉雷 组织，这项拟议的研究将识别和验证可能定向的特定免疫反应 组织特异性自身抗原。吴博士的假设是，受IRAE影响的组织中的自身免疫反应 是由CPIs新诱导的并且在治疗前不存在，以及负责IRAE的组织自身抗原 以一组不同的组织驻留T细胞和特定的自身抗体为靶标。该计划的目标是 建议的研究是：(1)分析自身反应性T细胞的抗原性和功能图谱 在受IRAE影响的组织中，(2)发现和验证对组织特异性自身抗原的自身抗体反应 与IRAE有关的信息。培训和研究计划包括有组织地将正式的 动态环境中的课程作业、教程、指导和实践研究体验 加州大学旧金山分校，著名的基础和翻译研究中心。吴博士的培训 将在癌症领域领先的翻译研究员劳伦斯·方博士的指导下进行 加州大学伯克利分校帕克癌症免疫治疗研究所的共同负责人，以及一位杰出的 医生-科学家顾问委员会，在每个领域都有丰富的指导经验和专业知识 与吴博士的培训和研究目标相对应。这项提案的中间目标是确定伊拉克- 将成为R01的基础的特定免疫反应。该奖项的长期目标是提供 使吴博士成为免疫疗法治疗的IRAE样本的机械研究的领导者的技能 使用新方法的患者，产生临床上有用的生物标志物和干预目标以供验证 在更大的临床试验中。

PROJECT SUMMARY/ABSTRACT The goal of this resubmission application is to train David Y. Oh, MD PhD, a medical oncologist and immunologist, providing him with the skills to become an independently funded laboratory investigator studying immune-related adverse events (IRAEs) after checkpoint inhibitors (CPIs). CPIs are cancer immunotherapies that activate anti-tumor immune responses leading to improved survival in several cancers, but also trigger IRAEs which are autoimmune responses against normal tissues that represent an increasing source of morbidity for cancer patients. The proposed training plan incorporates didactic and practical experience to provide a foundation in the following areas which complement his existing expertise and are critical to accomplishing his research goals: (1) fundamental B cell biology including B cell-driven autoimmunity and methods for autoantibody discovery and validation, (2) next-generation sequencing methods and analysis including single-cell approaches appropriate for human patient samples, (3) methods in clinical trial design including biostatistics and correlative science. The research plan addresses key limitations in our understanding of IRAE mechanisms by studying both cellular (T cell) as well as humoral (B cell) responses to autoantigens during IRAEs. By studying IRAE tissues, the proposed research will identify and validate the specific immune responses that may be directed towards tissue-specific autoantigens. Dr. Oh’s hypothesis is that autoimmune responses in IRAE-affected tissues are newly induced by CPIs and not present before treatment, and the tissue autoantigens responsible for IRAEs are targeted by a distinct subset of tissue-resident T cells and by specific autoantibodies. The Aims of the proposed research are: (1) to dissect the antigenic and functional profile of autoreactive T cells that are enriched in IRAE-affected tissues, and (2) to discover and validate autoantibody responses to tissue-specific autoantigens that are associated with IRAEs. The training and research plan encompass a structured combination of formal coursework, tutorials, mentorship, and hands-on research experience within the dynamic environment of the University of California, San Francisco, a renowned center for basic and translational research. Dr. Oh’s training will be conducted under the mentorship of Dr. Lawrence Fong, a leading translational researcher in cancer immunotherapies who co-directs the Parker Institute for Cancer Immunotherapy at UCSF, and a distinguished advisory committee of physician-scientists with extensive mentorship experience and expertise in each area corresponding to Dr. Oh’s training and research aims. The intermediate goal of this proposal is to identify IRAE- specific immune responses that will be the basis for an R01. The long-term goal of this award is to provide the skills to enable Dr. Oh to become a leader in mechanistic studies of IRAE samples from immunotherapy-treated patients using novel approaches, yielding clinically useful biomarkers and targets for intervention to be validated in larger clinical trials.