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Clin Cancer Res. 2015 Apr 1;21(7):1639-51. doi: 10.1158/1078-0432.CCR-14-2339. Epub 2015 Jan 14.

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.

Author information

1
Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
2
Molecular Medicine Unit, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
3
Statistical Science, GlaxoSmithKline, Collegeville, Pennsylvania.
4
Immuno-Oncology and Combination DPU, GlaxoSmithKline, Collegeville, Pennsylvania. axel.x.hoos@gsk.com.

Abstract

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.

PMID:
25589619
DOI:
10.1158/1078-0432.CCR-14-2339
[Indexed for MEDLINE]
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