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Sci Transl Med. 2015 Mar 18;7(279):279ra41. doi: 10.1126/scitranslmed.aaa4691.

Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.

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  • 1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
  • 2Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Division of Translational Oncology, Carlos III Health Institute, Madrid 28029, Spain.
  • 3Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.
  • 4Merck Research Laboratories, Boston, MA 02115, USA.
  • 5Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
  • 6Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.
  • 7Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA. aribas@mednet.ucla.edu.

Abstract

Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.

PMID:
25787767
PMCID:
PMC4765379
DOI:
10.1126/scitranslmed.aaa4691
[PubMed - indexed for MEDLINE]
Free PMC Article

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