Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma

Abstract

The combination of BRAF-targeted agents with immune checkpoint inhibitors represents a recent advance in the treatment of melanoma, even though each of these therapeutic approaches alone has specific limitations. Increasing evidence suggests indeed the existence of a synergistic interaction between these therapeutic modalities.

Keywords: BRAF; PDL1; checkpoint blockade; immunotherapy; melanoma.

Figure 1. Oncogenic BRAF contributes to immune escape through the downregulation of melanoma-differentiation antigens and by establishing an immunosuppressive tumor microenvironment. The administration of a BRAF inhibitor promotes clinical responses along with an increased expression of melanoma-differentiation antigens by malignant cells, an increased tumor infiltration by CD8⁺ T cells, and a decreased production of immunosuppressive cytokines such as interleukin (IL) -6, IL-8 and IL-1α as well as of the angiogenic mediator vascular endothelial growth factor (VEGF). This phenotype is reverted at time of disease progression. Importantly, the expression of immunomodulatory molecules on T cells (e.g., PD1) and on tumor cells (e.g., PDL1) is also increased within 14 d of BRAF-targeted therapy initiation. Taken together, these data suggest that the therapeutic potential of BRAF-targeted agents may be significantly improve by the early blockade of immune checkpoints.