Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges

Abstract

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF(V600) driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

Fig 1.

Effects of BRAF inhibitors on melanoma and immune cells. Melanoma tumor cells with a BRAF^V600E mutation experience a decrease in oncogenic mitogen-activated protein kinase (MAPK) pathway signaling when treated with a BRAF inhibitor, evidenced by phosphorylation of ERK (pERK). (A) In lymphocytes, the exposure to a BRAF inhibitor instead leads to a paradoxical activation of the MAPK pathway and increased phosphorylated ERK (pERK). (B) BRAF inhibitor therapy in melanoma cells has been reported to increase melanoma antigen expression and T-cell recognition directly or indirectly. (C) Chronic exposure to BRAF inhibitors has been shown to upregulate the surface expression of the immune checkpoint ligand (PD-L1) of programmed death receptor-1 (PD-1). (D) The tumor microenvironment (macrophages, tumor-associated fibroblasts [TAFs]) can be modulated by BRAF inhibitors to enhance the immune response. IL, interleukin; PD-1, programmed death receptor-1; MDSC, myeloid-derived suppressor cell; MEKi, MEK inhibitor; TCR, T-cell receptor; TIL, tumor-infiltrating lymphocyte; TNF-α, tumor necrosis factor alpha; Tyr, tyrosinase; VEGF, vascular endothelial growth factor.

Fig 2.

Distinct effects on the mitogen-activated protein kinase (MAPK) pathway signaling by BRAF and MEK inhibitors in BRAF-mutant and BRAF wild-type cells. (A) In BRAF-mutant melanoma cells, both BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) inhibit the MAPK pathway, resulting in increased apoptosis, tumor antigen expression, and decreased release and/or expression of suppressive cytokines and ligands (eg, interleukin-6, interleukin-10, transforming growth factor beta, programmed cell death protein 1 ligand). (B) BRAF inhibition in BRAF wild-type cells that have upstream MAPK signaling results in paradoxical activation of the MAPK pathway. This phenomenon can increase effector T or natural killer cell function but also has the potential to lead to exhaustion. Overreacting T cells could attack normal cells causing autoimmune toxicity. The paradoxical MAPK activation could also have the potential to increase immune suppressive cell functions (eg, myeloid-derived suppressor cells, T regulatory cells). (C) Adding a MEKi to the BRAFi in BRAF wild-type immune cells could decrease autoimmune toxicity or release of suppressive factors and inhibit immune suppressive cells. There might be detrimental effects on T-cell functions, but there is also the potential to balance the overexhausted T cells. P, phosporylation.