The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4
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DOI：
10.1158/1078-0432.ccr-14-2339
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发表时间：
2015-04-01
影响因子：
11.5
通讯作者：
Hoos, Axel
中科院分区：
文献类型：
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作者：
Liu, Li;Mayes, Patrick A.;Hoos, Axel
目的：评估达拉非尼和曲美替尼的体外免疫效应，并测试曲美替尼在体内是否增强或拮抗免疫调节抗体的活性。实验设计：在来自健康志愿者的人 CD4(+) 和 CD8(+) T 细胞、一组人类肿瘤细胞系以及使用 CT26 小鼠模型的体内评估达拉非尼和曲美替尼的免疫效应。结果：达拉非尼增强 pERK 表达水平，并且不抑制人类 CD4(+) 或 CD8(+) T 细胞功能。 Trametinib 降低了 pERK 水平，并导致 T 细胞增殖/细胞因子和免疫调节基因子集表达的部分/暂时抑制，这是依赖于环境的。添加达拉非尼可部分抵消曲美替尼的作用。 BRAF V600E/K 中的达拉非尼和曲美替尼以及 BRAF 野生型肿瘤细胞中的曲美替尼可诱导凋亡标志物，上调 HLA 分子表达，并下调某些免疫抑制因子，如 PD-L1、IL1、IL8、NT5E 和 VEGFA。体外获得对 BRAF 抑制的抗性后，肿瘤细胞中的 PD-L1 表达上调。在 CT26 模型中，曲美替尼与针对 PD-1、PD-L1 或 CTLA-4 的免疫调节剂的组合比任何单一药物更有效。 Trametinib 与抗 PD-1 药物联合使用可增加 CT26 肿瘤中的肿瘤浸润 CD8(+) T 细胞。并行或分阶段序贯治疗（定义为曲美替尼先导，随后曲美替尼加抗 PD-1 抗体）与抗 PD-1 抗体随后抗 PD-1 加曲美替尼相比，表现出更佳的疗效。结论：这些发现支持靶向治疗达拉非尼和曲美替尼与免疫调节抗体之间存在协同作用的潜力。这种联合治疗方案的临床探索正在进行中。 (C)2015 AACR。
Purpose: To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.Experimental Design: Immune effects of dabrafenib and trametinib were evaluated in human CD4(+) and CD8(+) T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.Results: Dabrafenib enhanced pERK expression levels and did not suppress human CD4(+) or CD8(+) T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immuno-suppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti-PD-1 increased tumor-infiltrating CD8(+) T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti-PD-1 antibody, demonstrated superior efficacy compared with anti-PD-1 antibody followed by anti-PD-1 plus trametinib.Conclusion: These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way. (C)2015 AACR.