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

项目总结/摘要 该提案包括一项研究和培训计划，将使黄博士从一个指导角色过渡到 独立调查员黄博士最近完成了他的血液学/肿瘤学奖学金， 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R 01资助的实验室，专注于反应机制， 对癌症免疫疗法的抵抗力。他的短期目标将通过K 08来实现，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长。在 此外，他还寻求获得大数据分析，临床试验设计和生物统计学的熟练程度。黄博士有 我选择了E博士。约翰·惠里是他的主要导师，塔拉·米歇尔博士是他的共同导师。Wherry博士是一个世界 在CD 8 T细胞生物学的领导者，包括CD 8 T细胞耗竭的转录组学和米切尔博士是一个 黑色素瘤临床试验者和宾夕法尼亚大学黑色素瘤研究项目的领导者。此外，他还组织了一个 由基础科学家、医生科学家和 生物统计学家，以支持他的研究方向和职业发展。 博士Huang最近在Nature上发表了抗PD-1治疗重振耗尽的CD 8 T细胞（TEX）， 可以在黑色素瘤患者的外周血中发现。这种免疫反应的强度 抗PD-1治疗产生的肿瘤负荷与患者的总体肿瘤负荷成比例，如通过 所有病人肿瘤长径的总和然而，肿瘤负荷大的患者 尽管产生了大量免疫反应，但抗PD-1治疗的结果仍较差。拟议 研究的重点是为什么抗PD-1治疗产生的大量免疫应答不足以控制一种疾病， 肿瘤负荷大。黄博士假设，高肿瘤负荷与定量和 抗PD-1产生的黑色素瘤特异性免疫应答的定性缺陷。因此，他将测试 高肿瘤负荷是否与1）黑色素瘤特异性免疫反应的强度和持续性降低有关？ 免疫应答（Aim 1），和2）从TEX向功能性记忆T细胞（TMEM）分化的缺陷（Aim 2）。 博士Huang将利用新辅助（术前）抗PD-1治疗的创新临床试验， 在抗PD-1之前和之后以及在肿瘤切除之后具有血液样品可用性的黑色素瘤。 这些研究将通过阐明高肿瘤负荷在肿瘤免疫治疗中的作用， 限制T细胞复苏，并建立治疗干预以减少肿瘤负荷的基本原理， 例如外科减瘤。提供的指导和培训将有效地将黄博士过渡到一个 独立的研究生涯，研究免疫治疗反应和耐药性的机制， 新型临床试验的背景。

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.