title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Stephen
authors.initials: S
authors.lastname: Eastman
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Sapna
authors.initials: S
authors.lastname: Yadavilli
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Tianqian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Laura
authors.initials: L
authors.lastname: Seestaller-Wehr
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Chris
authors.initials: C
authors.lastname: Hopson
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Lyuben
authors.initials: L
authors.lastname: Tsvetkov
authors.affiliation: Molecular Medicine Unit, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Junping
authors.initials: J
authors.lastname: Jing
authors.affiliation: Statistical Science, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: James
authors.initials: J
authors.lastname: Smothers
authors.affiliation: Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania. axel.x.hoos@gsk.com.
authors.forename: Axel
authors.initials: A
authors.lastname: Hoos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D010091:Oximes / Q000494:pharmacology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; D007093:Imidazoles; D007155:Immunologic Factors; D010091:Oximes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib