Pelster Meredith S, Amaria Rodabe N
The University of Texas MD Anderson Cancer Center, Department of Hematology/Oncology, Houston, TX, USA.
The University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology, 1515 Holcombe Boulevard, Unit 0430, Houston, TX 77030, USA.
Ther Adv Med Oncol. 2019 Feb 19;11:1758835919830826. doi: 10.1177/1758835919830826. eCollection 2019.
The development of BRAF and MEK inhibitors (BRAFis and MEKis) and immune checkpoint inhibitors have changed the management of advanced stage melanoma and improved the outcomes of patients with this malignancy. However, both therapeutic approaches have limitations, including a limited duration of benefit in subsets of BRAF-mutant melanoma patients treated with targeted therapy and a lower overall response rate without a clear predictive biomarker in patients treated with checkpoint inhibitors. Preclinical and translational data have shown that BRAFis and MEKis alter the tumor microenvironment to make it more amenable to immunotherapy and have provided the scientific rationale for combing BRAFis and MEKis with immunotherapy. In this review, the initial studies demonstrating the impact of BRAFis and MEKis on the expression of melanoma differentiation antigens, T-cell infiltration, and the balance of immune stimulatory and immune suppressive cells and cytokines are addressed. Preclinical work on the combination of targeted therapy with BRAFis and MEKis with immunotherapy are reviewed, highlighting improved tumor responses in mouse models of BRAF-mutated melanoma treated with combinatorial strategies. Lastly, data from early clinical trials of combined targeted therapy and immunotherapy are discussed, focusing on response rates and toxicities.
BRAF和MEK抑制剂（BRAFis和MEKis）以及免疫检查点抑制剂的研发改变了晚期黑色素瘤的治疗方式，并改善了这种恶性肿瘤患者的治疗效果。然而，这两种治疗方法都有局限性，包括接受靶向治疗的BRAF突变型黑色素瘤患者亚组的获益持续时间有限，以及接受检查点抑制剂治疗的患者总体缓解率较低且缺乏明确的预测生物标志物。临床前和转化研究数据表明，BRAFis和MEKis会改变肿瘤微环境，使其更适合免疫治疗，并为BRAFis和MEKis与免疫治疗联合应用提供了科学依据。在这篇综述中，我们讨论了最初的一些研究，这些研究证明了BRAFis和MEKis对黑色素瘤分化抗原表达、T细胞浸润以及免疫刺激和免疫抑制细胞及细胞因子平衡的影响。我们还回顾了BRAFis和MEKis靶向治疗与免疫治疗联合应用的临床前研究工作，突出了联合策略治疗BRAF突变型黑色素瘤小鼠模型时肿瘤反应的改善。最后，我们讨论了靶向治疗与免疫治疗联合应用的早期临床试验数据，重点关注缓解率和毒性。
