Immunomodulatory effects of BRAF and MEK inhibitors: Implications for Melanoma therapy

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.