J Natl Compr Canc Netw. 2018 Jun;16(6):782-790. doi: 10.6004/jnccn.2018.7049.
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer. The clinical impact of MCC has been increasing due to steadily rising incidence rates. Since 2001, more than 24,000 cases of MCC have been reported to the US National Program of Cancer Registries database, and in 2018, more than 2,500 incident cases are expected. MCC is highly aggressive, and one-third of patients will either present with or develop metastatic disease. Outcomes in patients with metastatic MCC have historically been poor; median time to progression with cytotoxic chemotherapy is only 3 months. MCC has long been appreciated to be immunogenic, with reports of spontaneous regression and responsiveness to immunotherapy. However, the mechanisms of this immunogenicity have only been understood over the past decade, with approximately 80% of cases in the United States associated with the Merkel cell polyomavirus (MCPyV) and expression of viral antigens (virus-positive [VP] MCC), and the remaining 20% of cases caused by UV radiation-induced damage leading to a high mutational burden and expression of neoantigens (virus-negative [VN] MCC). These insights have led to multiple successful trials of immunotherapies for MCC. PD-1 axis checkpoint inhibitors are now regarded as the preferred frontline systemic therapy in eligible patients (including both VP- and VN-MCC), with impressive frequency, durability, and depth of objective responses, which compare favorably to those of most solid tumors. This article reviews the safety and efficacy data from the key clinical trials of immune checkpoint inhibitors for metastatic MCC, and discusses several issues relevant to the clinical use of these agents. Finally, emerging immunotherapies for MCC, including cellular therapies and adjuvant systemic therapies, are reviewed.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种神经内分泌皮肤癌。由于发病率稳步上升，MCC 的临床影响一直在增加。自 2001 年以来，美国国家癌症登记处数据库已报告超过 24000 例 MCC 病例，2018 年预计将有超过 2500 例新发病例。MCC 侵袭性强，三分之一的患者会出现或发展为转移性疾病。历史上，转移性 MCC 患者的预后较差；细胞毒性化疗的中位无进展时间仅为 3 个月。MCC 一直被认为具有免疫原性，有自发消退和对免疫治疗有反应的报道。然而，这种免疫原性的机制仅在过去十年中才被理解，美国约 80%的病例与 Merkel 细胞多瘤病毒（Merkel cell polyomavirus，MCPyV）有关，并表达病毒抗原（病毒阳性 [VP] MCC），其余 20%的病例由紫外线辐射诱导的损伤引起，导致高突变负担和新抗原的表达（病毒阴性 [VN] MCC）。这些见解导致了针对 MCC 的多种成功的免疫治疗试验。PD-1 轴检查点抑制剂现在被认为是适合患者（包括 VP- 和 VN-MCC）的首选一线全身治疗方法，其客观反应的频率、持久性和深度令人印象深刻，与大多数实体瘤相比具有优势。本文综述了免疫检查点抑制剂治疗转移性 MCC 的关键临床试验的安全性和疗效数据，并讨论了与这些药物临床应用相关的几个问题。最后，还综述了用于 MCC 的新兴免疫疗法，包括细胞疗法和辅助全身疗法。
