Combination Immunotherapy Development in Melanoma.
Combination Immunotherapy Development in Melanoma.
复制标题
DOI：
10.1200/edbk_201131
复制
发表时间：
2018-05-23
期刊：
影响因子：
--
通讯作者：
Wargo, Jennifer
中科院分区：
文献类型：
--
作者：
Eggermont, Alexander M M;Crittenden, Marka;Wargo, Jennifer
黑色素瘤一直是推动实体瘤免疫治疗发展的最重要的癌症。自2010年以来，打破耐受性的概念使免疫疗法发生了革命性的变化。它代表了一个重大的范式转变，标志着一个新时代的开始。第一批免疫检查点抑制剂抗ctla -4和抗pd -1/抗pd - l1的影响是前所未有的。在7年的时间里，它将超过50%的晚期黑色素瘤患者转化为可治愈的疾病。另一个重要的进展是BRAF抑制剂与MEK抑制剂联合治疗BRAF突变型黑色素瘤。对于晚期疾病的治疗，免疫检查点抑制剂ipilimumab（2011年）、nivolumab（2014年）、pembrolizumab（2014年）、ipilimumab + nivolumab联合（2015年）和溶瘤病毒疫苗laherparepvec（2015年）获得批准。达非尼+曲美替尼联合治疗BRAF突变黑色素瘤于2014年获批，其他BRAF + MEK抑制剂联合治疗也取得了类似的成功。由于其独特的治疗指数（高效率和低毒），抗pd -1药物（nivolumab和pembrolizumab）现在已经被置于几乎所有黑色素瘤联合治疗发展策略的中心。抗pd -1药物是与多种其他免疫治疗药物联合使用的核心分子，如免疫检查点抑制剂、激动剂、IDO抑制剂、巨噬细胞极化剂、单克隆抗体、疫苗、靶向药物、化疗药物、放射治疗，甚至微生物组调节剂。
Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti-CTLA-4 and anti-PD-1/anti-PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas. For the treatment of advanced disease, approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014), the combination ipilimumab plus nivolumab (2015), and the oncolytic virus vaccine laherparepvec (2015). The combination dabrafenib plus trametinib for BRAF-mutant melanoma was approved in 2014, with similar success for other BRAF plus MEK inhibitor combinations. Because of its unique therapeutic index (high efficacy and low toxicity) anti-PD-1 agents (nivolumab and pembrolizumab) have now been placed at the center of practically all combination therapy development strategies in melanoma. Anti-PD-1 agents are the central molecule for combinations with a great variety of other immunotherapeutics such as immune checkpoint inhibitors, agonists, IDO inhibitors, macrophage polarizing agents, monoclonal antibodies, vaccines, targeted agents, chemotherapeutics, radiation therapy, and even microbiome modulators.