Role of tumor burden in limiting durable reinvigoration by PD-1 blockade

项目概要/摘要 该提案包括一项研究和培训计划，该计划将使黄博士从指导角色转变为 独立调查员。黄博士最近完成了他的血液学/肿瘤学研究金 宾夕法尼亚大学，目前是血液学/肿瘤学系的医学讲师。 他的长期目标是建立一个独立的 R01 资助实验室，重点研究响应机制和 对癌症免疫疗法的抵抗。他的短期目标将通过 K08 实现，包括 获得肿瘤全外显子组测序、新表位预测和转录组学方面的技术专业知识。在 此外，他还寻求精通大数据分析、临床试验设计和生物统计学。黄博士有 选择 E. John Wherry 博士作为他的主要导师，并选择 Tara Michell 博士作为他的共同导师。惠里博士是一个世界 Mitchell 博士是 CD8 T 细胞生物学（包括 CD8 T 细胞耗竭转录组学）领域的领导者 黑色素瘤临床试验员和宾夕法尼亚大学黑色素瘤研究项目的领导者。此外，他还组装了一个 由基础科学家、医师科学家和专家组成的强大且互补的指导委员会 生物统计学家支持他的研究方向和职业发展。 黄博士最近在《自然》杂志上发表文章称，抗PD-1疗法可以使耗尽的CD8 T细胞（TEX）重新焕发活力， 可以在黑色素瘤患者的外周血中进行鉴定。这种免疫反应的强度 抗 PD-1 疗法产生的肿瘤负荷与患者的总体肿瘤负荷成正比，测量结果如下： 患者所有肿瘤的长径总和。然而，肿瘤负担重的患者 尽管产生了大量的免疫反应，但抗 PD-1 治疗的结果不佳。拟议的 研究重点是为什么抗 PD-1 疗法产生的大量免疫反应不足以控制 肿瘤负荷大。黄博士推测，高肿瘤负荷与定量和 抗 PD-1 产生的黑色素瘤特异性免疫反应的质量缺陷。因此，他将测试 高肿瘤负荷是否与 1) 黑色素瘤特异性的程度和持久性降低有关 免疫反应 (Aim1)，以及 2) 从 TEX 分化为功能性记忆 T 细胞 (TMEM) 的缺陷 (Aim2)。 黄博士将利用新辅助（术前）抗 PD-1 疗法的创新临床试验 黑色素瘤在抗 PD-1 治疗前后以及肿瘤切除后可获得血液样本。 这些研究将通过阐明高肿瘤负荷在癌症免疫治疗中的作用来推进癌症免疫治疗领域的发展。 限制 T 细胞重生，并建立减少肿瘤负担的治疗干预的基本原理， 比如减瘤手术。所提供的指导和培训将有效地将黄博士转变为一名 独立研究生涯，研究免疫治疗反应和耐药机制 新颖的临床试验的背景。

Project Summary/Abstract This proposal encompasses a research and training plan that will transition Dr. Huang from a mentored role to an independent investigator. Dr. Huang recently completed his hematology/oncology fellowship at the University of Pennsylvania, and is currently an Instructor of Medicine in the Division of Hematology/Oncology. His long-term goal is to establish an independent R01 funded lab focusing on mechanisms of response and resistance to cancer immunotherapies. His short-term goals, that will be facilitated through the K08, include gaining technical expertise in tumor whole exome sequencing, neoepitope prediction, and transcriptomics. In addition, he seeks to gain proficiency in big data analysis, clinical trial design, and biostatistics. Dr. Huang has chosen Dr. E. John Wherry as his primary mentor and Dr. Tara Michell as his co-mentor. Dr. Wherry is a world leader in in CD8 T cell biology, including transcriptomics of CD8 T cell exhaustion and Dr. Mitchell is a melanoma clinical trialist and a leader of Penn's melanoma research program. In addition, he has assembled a strong and complementary mentoring committee composed of basic scientists, physician-scientists, and a biostatistician to support him in his research direction and career development. Dr. Huang has recently published in Nature that anti-PD-1 therapy reinvigorated exhausted CD8 T cells (TEX), that could be identified in the peripheral blood of melanoma patients. The magnitude of this immune response generated by anti-PD-1 therapy was proportional to the overall tumor burden of the patient, as measured by the sum of the long diameter of all of the patient's tumors. Yet, patients with a large burden of tumor have a poor outcome with anti-PD-1 therapy despite the generation of a large immune response. The proposed research focuses on why a large immune response generated by anti-PD-1 therapy is not sufficient to control a large tumor burden. Dr. Huang hypothesizes that that high tumor burden is associated with a quantitative and qualitative defect in the melanoma-specific immune response generated by anti-PD-1. Thus, he will test whether high tumor burden is associated with 1) a decreased magnitude and persistence of melanoma-specific immune response (Aim1), and 2) a defect in differentiation from TEX to functional memory T cells (TMEM) (Aim2). Dr. Huang will take advantage of an innovative clinical trial of neo-adjuvant (pre-surgical) anti-PD-1 therapy in melanoma with availability of blood samples before and after anti-PD-1, and after tumor resection. These studies will advance the field of cancer immunotherapy by elucidating the role of high tumor burden in limiting T cell reinvigoration, and establish the rationale for therapeutic interventions to reduce tumor burden, such as surgical debulking. The mentorship and training provided will effectively transition Dr. Huang to an independent research career studying the mechanisms of immunotherapy response and resistance in the context of novel clinical trials.