Immunobiology and Immune Therapyfor 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：
10629189
负责人：
PAUL NGHIEM
金额：
$ 255.68万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629189
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 Cancer Control 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 response Immunobiology Immunophenotyping Immunotherapy In Vitro Incidence 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 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-PD-L1 anti-tumor immune response antibody test antigen-specific T cells 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 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.

总体摘要：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团队以及多家机构的合作者在表征对这种很大程度上由病毒驱动的经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的临床试验，包括PD-1封锁，现在已成为标准的一部分护理这种侵略性疾病。这些努力最近导致将pembrolizumab（抗PD-1）纳入美国癌症护理的杰出指南以及有史以来第一个FDA批准MCC疗法 AVELUMAB（抗PD-L1）。尽管大约一半的患者从PD-1途径封锁中获得了长期受益，但对于近一半的晚期疾病患者，他们的需求仍然很大到PD-1途径封锁。我们提出了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根据MCC的这些最近的主要见解，以驱动癌症为基础。该建议旨在提高我们对患者为什么要对PD-1封锁疗法做出反应，以确定相关的免疫逃避机制，并确定并确定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存储库和关系数据库，我们准备解决两个范式转移问题：实用程序（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细胞亲和力，以及肿瘤内在的鉴定和先天免疫逃避机制（项目2），可以针对扩大适应性免疫反应 PD-1途径阻断难治性患者。项目1将识别高抗抗抗MCPYV T细胞，进行临床试验以测试用这些高避免性T的抗原特异性TCR转导的CD8 T细胞的安全性和功效细胞，并确定与这种尖端方法反应或无响应有关的机制。这项目2的总体目标是了解与成功或未能响应PD-1相关的机制路径封锁。通过获得并比较PD-1封锁治疗活检并进行比较他们是由领先的合作者团队进行的复杂研究，项目2将发现肿瘤的目标方面影响PD-1阻滞反应的生物学，T细胞生物学和先天免疫。项目3将大大扩展我们先前对对MCC的自适应免疫反应的研究，包括对病毒特异性的更详细的分析在MCC患者预后中起关键作用的CD8 T细胞。我们将扩大调查以包括肿瘤特异性 B细胞和CD4 T细胞的反应，因为我们最近开发了隔离和表征这些MCPYV-的工具特异性淋巴细胞。利用这些集体研究，该计划将为表征针对癌症抗原的肿瘤特异性免疫反应，这些免疫反应在MCC患者中共享，并发现对癌症至关重要的免疫逃避机制。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

DOI：
10.3390/cancers13143415
发表时间：
2021-07-08
期刊：
Cancers
影响因子：
5.2
作者：
Goff PH;Bhakuni R;Pulliam T;Lee JH;Hall ET;Nghiem P
通讯作者：
Nghiem P

Merkel cell carcinoma can be indolent: A case with 7 locoregional recurrences over 15 years highlights the importance of patient-tailored management.

DOI：
10.1016/j.jdcr.2021.08.009
发表时间：
2021-10
期刊：
JAAD case reports
影响因子：
0
作者：
Breneman A;Akaike T;Paulson KG;Breneman DL;Nghiem P
通讯作者：
Nghiem P

LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition.

DOI：
10.3389/fimmu.2023.1253568
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Buchta Rosean, Claire;Leyder, Erica C.;Hamilton, Jeneice;Carter, Joseph J.;Galloway, Denise A.;Koelle, David M.;Nghiem, Paul;Heiland, Teri
通讯作者：
Heiland, Teri

Management and Prognosis of Cardiac Metastatic Merkel Cell Carcinoma: A Case-Control Study and Literature Review.