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科学家提出针对BRAF突变黑色素瘤的免疫治疗方法
作者:小柯机器人 发布时间:2019/7/8 14:02:32

美国加州大学洛杉矶分校Antoni Ribas研究组的一项最新研究发现,针对BRAF突变型黑色素瘤的免疫治疗方法,使用BRAF和MEK抑制剂联合PD-1阻断剂具有良好的治疗效果。 这一研究成果于2019年发表在国际学术期刊《Nature Medicine》上。

研究组招募了15例BRAFV600突变的转移性黑色素瘤患者,进行了达巴非尼、曲米替尼和彭布洛里珠单抗(NCT02130466)的首次人体临床试验。11例患者(73%)发生3/4级治疗相关不良事件,最常见的是肝功能检测升高和发热,其中大多数通过停用抗pd -1抗体或靶向治疗联合用药解决。11例(73%;95%置信区间= 45-92%)有客观反应,有6例患者 (40%;95%置信区间= 16-68%)的平均随访时间为27个月(范围= 10.3-38.4 +个月)。这项研究表明,这种三重联合治疗可能通过增加长期抗肿瘤反应的频率,使BRAF600突变的转移性黑色素瘤患者受益。

研究人员表示,利用B-Raf原癌基因(BRAF)和丝裂原激活蛋白激酶激酶(MEK)抑制剂进行癌基因靶向治疗可在BRAFV600突变的黑色素瘤患者中诱导高的初始反应率,但平均反应时间约为1年。程序性死亡1 (PD-1)抗体免疫治疗的反应率较低,但反应时间较长。临床前模型表明,BRAF和MEK抑制剂联合PD-1阻断治疗可提高抗肿瘤活性,这可能为那些不太可能对任何一种单独治疗方式产生长期反应的患者提供额外的治疗选择。

附:英文原文

Title: Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF -mutant melanoma

Author: Antoni Ribas, Donald Lawrence, Victoria Atkinson, Sachin Agarwal, Wilson H. Miller, Matteo S. Carlino, Rosalie Fisher, Georgina V. Long, F. Stephen Hodi, Jennifer Tsoi, Catherine S. Grasso, Bijoyesh Mookerjee, Qing Zhao, Razi Ghori, Blanca Homet Moreno, Nageatte Ibrahim, Omid Hamid

Issue&Volume: Volume 25 Issue 6,June 2019

Abstract: Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab (NCT02130466). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval=45–92%) had an objective response, and six (40%; 95% confidence interval=16–68%) continued with a response at a median follow-up of 27months (range=10.3–38.4+months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

DOI: 10.1038/s41591-019-0476-5

Source: https://www.nature.com/articles/s41591-019-0476-5

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex