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

项目摘要/摘要 这项建议包括一项研究和培训计划，将黄博士从指导角色转变为 一名独立调查员。黄医生最近在纽约大学完成了他的血液学/肿瘤学研究 现为美国宾夕法尼亚大学血液科/肿瘤科医学讲师。 他的长期目标是建立一个由R01资助的独立实验室，专注于反应机制和 对癌症免疫疗法的抵抗。他的短期目标，将通过K08促进，包括 在肿瘤全外显子组测序、新表位预测和转录学方面获得技术专长。在……里面 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·约翰·惠瑞博士作为他的主要导师，塔拉·米切尔博士作为他的共同导师。惠瑞博士是一个世界 在CD8 T细胞生物学方面的领导者，包括CD8 T细胞耗竭的转录组学，米切尔博士是 黑色素瘤临床试验专家，宾夕法尼亚大学黑色素瘤研究项目负责人。此外，他还组建了一个 由基础科学家、内科科学家和 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疗法使耗尽的CD8 T细胞(TeX)重新焕发活力。 这可以在黑色素瘤患者的外周血液中识别出来。这种免疫反应的大小 抗PD-1治疗产生的肿瘤与患者的总体肿瘤负担成正比，通过 患者所有肿瘤的长径之和。然而，有很大肿瘤负担的患者 尽管产生了很大的免疫反应，但抗PD-1治疗的结果很差。建议数 研究的重点是为什么抗PD-1治疗产生的大量免疫反应不足以控制 巨大的肿瘤负担。黄博士假设，高肿瘤负担与数量和 抗PD-1抗体产生的黑色素瘤特异性免疫反应存在质的缺陷。因此，他将测试 高肿瘤负担是否与1)黑色素瘤特异性的数量减少和持久性有关 免疫应答(Aim1)；2)T细胞向功能性记忆T细胞(TMEM)分化缺陷(AIM2)。 黄博士将利用新辅助(手术前)抗PD-1疗法的创新临床试验 抗PD-1前后和肿瘤切除后血液样本可用的黑色素瘤。 这些研究将通过阐明高肿瘤负担在癌症免疫治疗中的作用来推动癌症免疫治疗领域的发展 限制T细胞的再生，并建立治疗干预以减轻肿瘤负担的理论基础， 比如外科手术去。所提供的指导和培训将有效地将黄博士转变为 独立的研究生涯，研究免疫治疗的反应和耐药机制 新的临床试验的背景。

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.