Immunobiology and Immune Therapy for Merkel Cell Carcinoma

默克尔细胞癌的免疫生物学和免疫治疗

基本信息

批准号：
9906874
负责人：
PAUL NGHIEM
金额：
$ 299.62万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/9906874
关键词：
Accounting Address Adoptive Transfer Affect Affinity Age Antibodies Antigens Autoimmune Process 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 Xenograft Model Xenograft procedure adaptive immune response adaptive immunity advanced disease anti-PD-1 anti-tumor immune response 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 outreach programmed cell death protein 1 programs relational database repository resistance mechanism response safety testing sex standard of care success tool transcriptomics tumor

项目摘要

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，在描述针对这种主要由病毒驱动且常常致命的皮肤癌的免疫反应。我们已经建立了针对关键免疫途径（包括 PD-1 阻断）的临床试验现已成为标准的一部分护理这种侵袭性疾病。这些努力最近导致派姆单抗（抗 PD-1）被纳入美国癌症护理的卓越指南以及 FDA 首次批准 MCC 疗法， 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，对于近一半没有持续反应的晚期疾病患者来说，仍然存在巨大的未满足的需求 PD-1 通路阻断。我们提出高度集中和综合的努力，以增进我们对免疫原性和病原体的理解基于 MCC 最近的这些重要见解来驱动癌症。该提案旨在加深我们对为什么患者对 PD-1 阻断治疗有反应或没有反应，以确定相关的免疫逃避机制，并确定并优先考虑可能对这种疾病和其他免疫原性癌症有益的治疗方法。利用默克尔细胞多瘤病毒 (MCPyV) 诱导的 MCC 的独特生物学特性以及我们广泛的样本库和关系数据库，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）控制癌症的功能性、抗原特异性 T 细胞亲和力，以及肿瘤内在和先天免疫逃避机制（项目 2）可用于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，进行临床测试用来自这些高亲和力 T 的抗原特异性 TCR 转导的 CD8 T 细胞的安全性和有效性的试验细胞，并确定与这种尖端方法有反应或无反应有关的机制。这项目 2 的总体目标是了解与 PD-1 反应成功或失败相关的机制通路封锁。通过获取和比较连续的 PD-1 阻断治疗前后的活组织检查并进行由领先的合作团队进行复杂的研究，项目 2 将揭示肿瘤的可靶向方面影响 PD-1 阻断反应的生物学、T 细胞生物学和先天免疫。项目3将大幅扩展我们之前对 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 CD8 T 细胞在 MCC 患者预后中发挥关键作用。我们将扩大我们的研究范围以包括肿瘤特异性 B 细胞和 CD4 T 细胞的反应，因为我们最近开发了工具来分离和表征这些 MCPyV- 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描述针对 MCC 患者共有的癌症抗原的肿瘤特异性免疫反应，揭示免疫逃避机制，这对更广泛的癌症很重要。