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 CTLA-4 antibody ipilimumab was terminated early due to substantial liver toxicities. MEK 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 BRAFV600E driven melanoma, 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 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 combination of dabrafenib, trametinib with anti-PD1 therapy in SM1 tumors, and observed superior anti-tumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma.

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

“…In fact, concurrent administration of BRAF and MEK inhibitors with ACT resulted in dramatic tumor response, increased T-cell infiltration, and effector functions in a syngeneic immunocompetent melanoma mouse model [114]. This was accompanied by increase in melanoma-associated antigens [114].…”

“…In fact, concurrent administration of BRAF and MEK inhibitors with ACT resulted in dramatic tumor response, increased T-cell infiltration, and effector functions in a syngeneic immunocompetent melanoma mouse model [114]. This was accompanied by increase in melanoma-associated antigens [114]. However, MEK inhibition was able to overcome the increase in intratumoral T-regulatory cells and macrophages observed after treatment with BRAF and ACT [114].…”

“…This was accompanied by increase in melanoma-associated antigens [114]. However, MEK inhibition was able to overcome the increase in intratumoral T-regulatory cells and macrophages observed after treatment with BRAF and ACT [114]. In a clinical context, the concomitant treatment with an MEK inhibitor was able to restore melanoma-associated antigen expression and CD8 T-cell infiltration in a patient experiencing progression following BRAF inhibition [94].…”

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

“…In mice, antibody-mediated blockade of CTLA-4 induces complete tumor rejection and immunologic memory in several murine models of cancer (14). In addition, preclinical murine studies have shown that CTLA-4 blockade synergizes with radiation therapy (15), chemotherapy (16), molecularly targeted therapy (17), and tumor vaccination (18) to eradicate established tumors. Mechanistic studies in mice have shown that CTLA-4 blockade increases the ratio of effector T-cells to Foxp3+ Treg cells in tumors (19).…”

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375

“…The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma and can be used in about one half of patients but they mostly develop resistance a few months after initiation [3,4,5]. Approximately 19-58% of patients with metastasis of melanoma benefit from a systemic immunotherapy, depending on mono- or combination therapy [6,7].…”