PT  - JOURNAL ARTICLE
AU  - Liu, Li
AU  - Mayes, Patrick A.
AU  - Eastman, Stephen
AU  - Shi, Hong
AU  - Yadavilli, Sapna
AU  - Zhang, Tianqian
AU  - Yang, Jingsong
AU  - Seestaller-Wehr, Laura
AU  - Zhang, Shu-Yun
AU  - Hopson, Chris
AU  - Tsvetkov, Lyuben
AU  - Jing, Junping
AU  - Zhang, Shu
AU  - Smothers, James
AU  - Hoos, Axel
TI  - 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
AID  - 10.1158/1078-0432.CCR-14-2339
DP  - 2015 Apr 01
TA  - Clinical Cancer Research
PG  - 1639--1651
VI  - 21
IP  - 7
4099  - http://clincancerres.aacrjournals.org/content/21/7/1639.short
4100  - http://clincancerres.aacrjournals.org/content/21/7/1639.full
SO  - Clin Cancer Res2015 Apr 01; 21
AB  - 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 immunosuppressive 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. Clin Cancer Res; 21(7); 1639–51. ©2015 AACR.