Immunobiology and Immune Therapyfor Merkel Cell Carcinoma

默克尔细胞癌的免疫生物学和免疫治疗

• 批准号: 10380816
• 负责人: PAUL NGHIEM
• 金额: $ 291.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-04 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380816
• 关键词: Accounting; Address; Adoptive Transfer; Affect; Affinity; Age; Antigens; Autoimmune; Avidity; B-Lymphocytes; Bioinformatics; Biological; Biological Specimen Banks; Biology; Biometry; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cellular biology; Clinical; Clinical Trials; Combined Modality Therapy; Core Biopsy; Data; Databases; Disease; Etiology; Experimental Designs; FDA approved; Failure; Flow Cytometry; Genetic; Goals; Guidelines; Immune; Immune Evasion; Immune Targeting; Immune response; Immunobiology; Immunophenotyping; Immunotherapy; In Vitro; Induced Mutation; Institution; Investigation; Knowledge; Leadership; Lymphocyte; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Modeling; Molecular; Molecular Analysis; Natural Immunity; Outcome; PD-1 blockade; PD-1 pathway; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Penetration; Phase I/II Trial; Phenotype; Play; Polyomavirus; Population; Positioning Attribute; Process; Prospective cohort; Refractory; Research; Resistance; Resources; Risk; Role; Safety; Skin Cancer; Specimen; Specimen Handling; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Transgenic Organisms; Tumor Antigens; Tumor Biology; Tumor Cell Biology; Tumor Immunity; UV induced; Virus; adaptive immune response; adaptive immunity; advanced disease; anti-PD-1; anti-tumor immune response; antibody test; antigen-specific T cells; base; cancer care; cellular transduction; experimental analysis; histological specimens; immune checkpoint blockade; immunogenic; improved; insight; meetings; member; mortality; multidimensional data; multimodality; novel; novel strategies; pathogen; patient derived xenograft model; patient outreach; pembrolizumab; programmed cell death protein 1; programs; relational database; repository; resistance mechanism; response; safety testing; sex; standard of care; success; tool; transcriptomics; tumor

OVERALL SUMMARY: IMMUNOBIOLOGY AND IMMUNE THERAPY FOR MERKEL CELL CARCINOMA Our Seattle-based MCC team, together with collaborators at several institutions, has played a leading role in characterizing the immune response against this largely virus-driven often-lethal skin cancer. We have established clinical trials targeting critical immune pathways including PD-1 blockade that have now become part of the standard of care for this aggressive disease. These efforts have recently led to the inclusion of pembrolizumab (anti-PD-1) in the preeminent guidelines for cancer care in the US and to the first-ever FDA approval for a therapy for MCC, avelumab (anti-PD-L1). Although approximately half of patients derive long-term benefit from PD-1 pathway blockade, there remains great unmet need for the nearly half of patients with advanced disease who do not persistently respond to PD-1 pathway blockade. We propose a highly focused and integrated effort to advance our understanding of immunogenic and pathogen- driven cancers based on these recent major insights in MCC. This proposal seeks to advance our understanding of why patients do or do not respond to PD-1 blockade therapy, to determine relevant immune evasion mechanisms, and to identify and prioritize therapies likely to be beneficial for this disease and other immunogenic cancers. Utilizing the unique biology of Merkel cell polyomavirus (MCPyV)-induced MCC and our extensive Specimen Repository and Relational Database, we are poised to address two paradigm-shifting issues: the utility (Project 1) and importance (Project 3) of functional, antigen-specific T cell avidity in controlling cancer, and the identification of tumor-intrinsic and innate immune-evasion mechanisms (Project 2) that can be targeted to broaden the adaptive immune response in PD-1 pathway blockade refractory patients. Project 1 will identify high-avidity anti-MCPyV T cells, conduct a clinical trial to test the safety and efficacy of CD8 T cells transduced with the antigen-specific TCRs from these high-avidity T cells, and determine the mechanisms involved with response or non-response to this cutting-edge approach. The overarching goal of Project 2 is to understand the mechanisms associated with success or failure to respond to PD-1 pathway blockade. By obtaining and comparing serial pre- and post-PD-1 blockade treatment biopsies and subjecting them to sophisticated studies by a leading team of collaborators, Project 2 will uncover targetable aspects of tumor biology, T cell biology, and innate immunity that affect the response to PD-1 blockade. Project 3 will greatly expand our prior studies of the adaptive immune response to MCC to include a far more detailed analysis of virus-specific CD8 T cells that play a key role in MCC patient outcomes. We will broaden our investigation to include tumor-specific responses by B cells and CD4 T cells, as we have recently developed tools to isolate and characterize these MCPyV- specific lymphocytes. Leveraging these collective studies, this Program will provide a unique opportunity to characterize the tumor-specific immune response against cancer antigens that are shared across MCC patients and uncover mechanisms of immune evasion that will be important for cancers more broadly.

总体总结：默克尔细胞癌的免疫生物学和免疫治疗 我们位于西雅图的MCC团队与多家机构的合作者一起，在以下方面发挥了主导作用： 描述了针对这种主要由病毒驱动的致命皮肤癌的免疫反应。我们建立 针对关键免疫途径的临床试验，包括PD-1阻断，现已成为标准的一部分 对这种侵袭性疾病的治疗这些努力最近导致帕博利珠单抗（抗PD-1）被纳入 美国卓越的癌症治疗指南和FDA首次批准的MCC治疗， avelumab（抗PD-L1）。尽管大约一半的患者从PD-1通路阻断中获得长期获益， 对于近一半的晚期疾病患者， PD-1通路阻断。 我们提出了一个高度集中和综合的努力，以促进我们对免疫原性和病原体的理解- 基于MCC最近的主要见解。这一建议旨在促进我们对以下问题的理解： 为什么患者对PD-1阻断治疗有反应或无反应，以确定相关的免疫逃避机制， 并确定和优先考虑可能对这种疾病和其他免疫原性癌症有益的疗法。利用 默克尔细胞多瘤病毒（MCPyV）诱导的MCC的独特生物学和我们广泛的标本库， 关系数据库，我们准备解决两个范式转换问题：实用性（项目1）和重要性 （项目3）在控制癌症中的功能性抗原特异性T细胞亲合力，以及肿瘤内在和 先天免疫逃避机制（项目2），可以有针对性地扩大适应性免疫反应， PD-1通路阻断难治性患者。项目1将鉴定高亲和力抗MCPyV T细胞，进行临床试验， 一项测试用来自这些高亲和力T细胞的抗原特异性TCR转导的CD 8 T细胞的安全性和功效的试验。 细胞，并确定与响应或不响应这一尖端方法所涉及的机制。的 项目2的总体目标是了解与PD-1应答成功或失败相关的机制 通路阻断通过获得和比较PD-1阻断治疗前后的系列活检， 通过领导团队的合作者进行的复杂研究，项目2将揭示肿瘤的靶向方面， 生物学、T细胞生物学和影响对PD-1阻断的应答的先天免疫。项目3将大大扩展 我们先前对MCC的适应性免疫反应的研究包括对病毒特异性的更详细的分析， CD 8 T细胞在MCC患者结局中发挥关键作用。我们将扩大研究范围， B细胞和CD 4 T细胞的反应，因为我们最近开发了分离和表征这些MCPyV的工具。 特异性淋巴细胞利用这些集体研究，该计划将提供一个独特的机会， 表征针对MCC患者共有的癌抗原的肿瘤特异性免疫应答， 揭示免疫逃避的机制，这对更广泛的癌症很重要。