title: Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.
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.
authors: Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors: Siwen
authors: S
authors: Hu-Lieskovan
authors: Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors: Stephen
authors: S
authors: Mok
authors: Division 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.
authors: Blanca
authors: B
authors: Homet Moreno
authors: Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.
authors: Jennifer
authors: J
authors: Tsoi
authors: Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors: Lidia
authors: L
authors: Robert
authors: Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors: Lucas
authors: L
authors: Goedert
authors: Merck Research Laboratories, Boston, MA 02115, USA.
authors: Elaine M
authors: EM
authors: Pinheiro
authors: Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors: Richard C
authors: RC
authors: Koya
authors: Crump 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.
authors: Thomas G
authors: TG
authors: Graeber
authors: Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.
authors: Begoña
authors: B
authors: Comin-Anduix
authors: Division 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.
authors: Antoni
authors: A
authors: Ribas
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007167:Immunotherapy / Q000379:methods*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D008285:Major Histocompatibility Complex; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010091:Oximes / Q000737:chemistry; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000276:immunology; D011728:Pyridones / Q000737:chemistry; D011744:Pyrimidinones / Q000737:chemistry; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007093:Imidazoles; D010091:Oximes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib