Hassel Jessica C, Zimmer Lisa, Sickmann Thomas, Eigentler Thomas K, Meier Friedegund, Mohr Peter, Pukrop Tobias, Roesch Alexander, Vordermark Dirk, Wendl Christina, Gutzmer Ralf
Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany.
Department of Dermatology, University Hospital Essen, 45147 Essen, Germany.
Cancers (Basel). 2023 Jun 30;15(13):3448. doi: 10.3390/cancers15133448.
Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.
针对无进展生存期和总生存期的4年及5年随访数据表明，接受抗程序性死亡蛋白（PD）导向的免疫检查点抑制剂治疗的黑色素瘤患者具有持久的临床获益。然而，至少有一半的患者对治疗无反应，或在初始治疗反应后出现早期或晚期复发。关于免疫治疗原发性和/或继发性耐药的原因以及复发模式，目前知之甚少。本综述由一个跨学科专家小组撰写，描述了对PD-1治疗反应的评估和耐药分类，简要总结了潜在的耐药机制，并分析了对免疫检查点抑制剂耐药的黑色素瘤患者的医疗需求和治疗选择。我们评估了转移性、辅助性和新辅助性治疗试验的临床数据，以列出耐药频率。对于这三种治疗情况，我们批判性地讨论了耐药预测生物标志物的作用，以及可能帮助患者克服免疫检查点治疗耐药的多模式治疗选择或新型免疫治疗方法。缺乏合适的生物标志物以及目前用于克服耐药的新型治疗方案（大多数以PD-1为基础）效果有限，支持我们建议将尽可能多的患者纳入新的或正在进行的临床试验。
