Homet Moreno Blanca, Mok Stephen, Comin-Anduix Begonya, Hu-Lieskovan Siwen, Ribas Antoni
Department of Medicine; Division of Hematology/Oncology; University of California, Los Angeles (UCLA) ; Los Angeles, CA USA.
Department of Molecular and Medical Pharmacology; University of California, Los Angeles (UCLA) ; Los Angeles, CA USA.
Oncoimmunology. 2015 Aug 17;5(7):e1052212. doi: 10.1080/2162402X.2015.1052212. eCollection 2016 Jul.
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAF (V600E) driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8(+) tumor infiltrating lymphocytes (TILs), as well as CD4(+) T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAF (V600E) mutant metastatic melanoma.
BRAF和MEK抑制剂的联合靶向治疗已成为BRAF（V600E）突变型黑色素瘤患者的标准治疗方案，但疗效并不持久。此外，抗PD-1和抗PD-L1抗体（Ab）在经过大量预处理的转移性黑色素瘤患者中展现出显著的临床益处，并且与单药治疗组相比，达拉非尼、曲美替尼和抗PD-1联合使用具有协同效应，这支持了基于PD-1阻断将达拉非尼、曲美替尼和免疫疗法联合应用可能是治疗转移性黑色素瘤的一种有效方法的观点。利用我们同基因BRAF（V600E）驱动的黑色素瘤小鼠模型（SM1），我们测试了添加靶向CD137（4-1BB）和/或CD134（OX40）的免疫刺激抗体是否会增强达拉非尼、曲美替尼和抗PD-1或抗PD-L1治疗的抗肿瘤效果。体外研究表明，达拉非尼、曲美替尼和抗PD-1联合治疗组可增加CD8(+)肿瘤浸润淋巴细胞（TILs）以及CD4(+) T细胞和肿瘤相关巨噬细胞（TAM）。在达拉非尼、曲美替尼和抗PD-1联合治疗中观察到PD-L1上调。达拉非尼、曲美替尼和抗PD-1与抗CD137或抗CD134联合使用显示出更强的抗肿瘤效果，但五药联合方案并不优于四药联合方案。总之，达拉非尼、曲美替尼、抗PD1或抗PD-L1联合治疗可产生强大的抗肿瘤活性，添加免疫刺激抗体抗CD137或抗CD134可进一步增强该活性。我们的研究结果支持在BRAF（V600E）突变型转移性黑色素瘤患者中对这些联合方案进行试验。
