Immunobiology and Immune Therapyfor Merkel Cell Carcinoma

Merkel细胞癌的免疫生物学及免疫治疗研究进展 我们位于西雅图的MCC团队与几个机构的合作者一起，在 描述了对这种主要由病毒驱动、通常是致命的皮肤癌的免疫反应。我们已经确立了 针对关键免疫途径的临床试验，包括PD-1阻断，现在已经成为标准的一部分 对这种侵袭性疾病的护理。这些努力最近导致将pembrolizumab(抗PD-1)纳入 美国卓越的癌症护理指南，以及FDA首次批准的MCC治疗方法， Avelumab(抗PD-L1)。虽然大约一半的患者从PD-1通路阻断中获得长期好处， 近一半的晚期疾病患者没有持久的反应，他们的需求仍然很大，没有得到满足 阻断PD-1通路。 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最近的这些重大见解而引发的癌症。这项建议旨在增进我们对 为什么患者对PD-1阻断治疗有或没有反应，以确定相关的免疫逃避机制， 并确定可能对本病和其他免疫原性癌症有益的治疗方法并确定其优先顺序。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储存库和 关系数据库，我们准备解决两个范式转换的问题：效用(项目1)和重要性 (项目3)功能性、抗原特异性T细胞亲和力在控制癌症中的作用，以及识别肿瘤固有的和 先天免疫-逃避机制(项目2)，可作为扩大适应性免疫反应的目标 PD-1通路阻断难治性患者。项目1将鉴定高亲和力的抗MCPyV T细胞，进行临床 用来自这些高亲和力T细胞的抗原特异性TCR转导CD8 T细胞的安全性和有效性的试验 细胞，并确定与响应或不响应这一尖端方法有关的机制。这个 项目2的首要目标是了解与PD-1反应成功或失败相关的机制 通道被封锁。通过获得和比较PD-1阻断治疗前后的连续活检组织和受试者 由一个领先的合作者团队进行的复杂研究，项目2将揭示肿瘤的靶向方面 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将大大扩展 我们之前对MCC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细胞对MCC患者的预后起着关键作用。我们将扩大我们的调查范围，以包括肿瘤特异性 B细胞和CD4T细胞的反应，因为我们最近开发了工具来分离和鉴定这些MCPyV- 特定的淋巴细胞。利用这些集体研究，该计划将提供一个独特的机会 描述MCC患者之间共有的针对癌症抗原的肿瘤特异性免疫反应 揭示免疫逃避的机制，这对更广泛的癌症来说将是重要的。

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.