Immunomodulatory effects of BRAF and MEK inhibitors: Implications for Melanoma therapy. (October 2018)

• Record Type: Journal Article
• Authors: Kuske, Marvin; Westphal, Dana; Wehner, Rebekka; Schmitz, Marc; Beissert, Stefan; Praetorius, Christian; Meier, Friedegund
• Is Part Of: Pharmacological research. Volume 136(2018)
• Page Start: 151
• Page End: 159
• Publication Date: 2018-10
• Subjects: Binimetinib (PubChem CID: 10288191) -- Cobimetinib (PubChem CID: 16222096) -- Dabrafenib (PubChem CID: 44462760) -- Encorafenib (PubChem CID: 50922675) -- Trametinib (PubChem CID: 11707110) -- Vemurafenib (PubChem CID: 42611257); ATC adoptively transferred T cells -- BRAFi BRAF inhibitors -- CCL2 chemokine ligand 2 -- CTLA-4 cytotoxic T-lymphocyte-associated protein 4 -- DC dendritic cells -- DLT dose-limiting toxicities -- HLA human leukocyte antigen -- IFNγ interferon gamma -- irAE immune-related adverse events -- LDH lactate-dehaydrogenase -- MDSCs myeloid-derived suppressor cells -- MEKi MEK inhibitors -- ORR overall response rates -- OS Overall survival -- PD-1 programmed cell death protein 1 -- PD-L1 programmed cell death 1 ligand 1 -- PD-L2 programmed cell death 1 ligand 2 -- PFS progression-free survival -- TIDS tumor infiltrating dendritic cells -- TIM-3 T cell immunoglobulin and mucin-domain containing-3 -- Tregs regulatory T cells; Immunological effects -- BRAF -- MEK -- Melanoma -- Targeted therapy -- Immunotherapy; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.08.019
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Targeted therapy with BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) provides rapid disease control with high response rates in patients with BRAF-mutant metastatic melanoma. However, the majority of patients develop resistance to therapy during the course of therapy. Immune checkpoint inhibitors show a slower onset of action with lower response rates, with responders showing sustained response. The combination of BRAFi/MEKi and immune checkpoint inhibitors combines the hope for a fast, reliable and lasting response to therapy. Preclinical data supports this hypothesis. With the help of the PubMed database, a comprehensive search and analysis of preclinical and clinical studies on the combination of BRAFi/MEKi with immune checkpoint inhibitors was performed and yielded the following results: 1) In vivo, BRAFi and MEKi have no negative effects on immune cells; BRAFi and MEKi generate 2) an immune stimulating tumor microenvironment, 3) an increased infiltration of immune cells into the tumors, 4) a better recognition of melanoma cells by immune effector cells, and 5) a better functionality of the immune effector cells. In addition, in vivo experiments 6) demonstrated a superiority of the combination treatment compared to the individual strategies in both BRAF-mutant and BRAF wild-type melanomas. In summary, available data show that both BRAFi and MEKi have beneficial effects on the antitumor immunity and the tumor microenvironment as a whole, which is mediated by different mechanisms. Currently, clinical studies are underway to investigate combinations of BRAFi and MEKi with immune checkpoint inhibitors. The results of these studies are eagerly awaited.