Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

被引:162
作者
Hu-Lieskovan, Siwen [1 ]
Robert, Lidia [1 ]
Moreno, Blanca Homet [1 ,2 ]
Ribas, Antoni [1 ]
机构
[1] Univ Calif Los Angeles, Los Angeles, CA 90095 USA
[2] Carlos III Hlth Inst, Madrid, Spain
基金
美国国家卫生研究院;
关键词
T-CELL TRANSFER; METASTATIC MELANOMA; TUMOR MICROENVIRONMENT; ANTIGEN-EXPRESSION; ANTITUMOR-ACTIVITY; SIGNALING PATHWAY; IMPROVED SURVIVAL; MEK INHIBITION; RAS MUTATIONS; VEMURAFENIB;
D O I
10.1200/JCO.2013.52.1377
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF(V600) driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials. (C) 2014 by American Society of Clinical Oncology
引用
收藏
页码:2248 / 2254
页数:7
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