Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA.
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Ther Adv Med Oncol. 2015 Mar;7(2):97-106. doi: 10.1177/1758834014567469.
Melanoma has historically been considered a refractory disease with few if any options in the advanced/metastatic setting. Advances in both immune and genetically targeted treatment approaches have revolutionized the spectrum of treatment options for melanoma patients over the last several years. Recently, checkpoint inhibition has become a major focus in the immune-based therapy of cancer, especially melanoma. This concept involves inhibition of regulatory cell surface molecules which act normally to dampen or modulate T-cell activation. Cancer, including melanoma, takes advantage of this physiologic mechanism to turn off T-cell activation and prevent effective T-cell antitumor responses. Checkpoint inhibitors such as anti cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti programmed death-1 (PD-1) can reverse this immune suppression and release T-cell activation. Nivolumab, a monoclonal antibody to the PD-1 receptor, promotes antitumor immunity by removing this key negative regulator of T-cell activation. In phase I/II studies, promising activity and safety have been observed and ongoing phase III trials are comparing nivolumab with other standard of care therapies (chemotherapy, ipilimumab). Efficacy may be even further increased when used in combination with ipilimumab (albeit with increased toxicity). In contrast to typical short-lived responses with cancer therapy in metastatic solid tumors, many responses induced by nivolumab appear durable. In this review, we discuss the evolution of immune therapy in melanoma leading to the development of nivolumab, the clinical experience with this agent, and its future development and clinical potential.
黑色素瘤一直被认为是一种难治性疾病，在晚期/转移性疾病中，如果有治疗选择的话也寥寥无几。近年来，免疫治疗和基因靶向治疗方法的进步彻底改变了黑色素瘤患者的治疗选择范围。最近，检查点抑制已成为癌症免疫治疗的主要焦点，尤其是黑色素瘤。这一概念涉及抑制调节性细胞表面分子，这些分子通常会抑制或调节 T 细胞的激活。癌症，包括黑色素瘤，利用这种生理机制来关闭 T 细胞的激活并阻止有效的 T 细胞抗肿瘤反应。检查点抑制剂，如抗细胞毒性 T 淋巴细胞抗原 4（抗 CTLA-4）和抗程序性死亡受体-1（PD-1），可以逆转这种免疫抑制，释放 T 细胞的激活。Nivolumab 是一种针对 PD-1 受体的单克隆抗体，通过去除 T 细胞激活的关键负调节因子，促进抗肿瘤免疫。在 I/II 期研究中，观察到了有希望的疗效和安全性，正在进行的 III 期试验正在比较 nivolumab 与其他标准治疗方法（化疗、ipilimumab）。当与 ipilimumab 联合使用时（尽管毒性增加），疗效可能进一步提高。与转移性实体瘤中癌症治疗的典型短暂反应不同，许多由 nivolumab 诱导的反应似乎是持久的。在这篇综述中，我们讨论了黑色素瘤免疫治疗的发展导致 nivolumab 的开发，该药物的临床经验及其未来的发展和临床潜力。
