BRAF(V600) Inhibitor GSK2118436 Targeted Inhibition of Mutant BRAF in Cancer Patients Does Not Impair Overall Immune Competency

Abstract

An intact immune system likely contributes to the outcome of treatment and may be important for clearance of drug-resistant tumor cells and for prevention of recurrence. Although pharmacologic inhibition of BRAF(V600E) in melanoma patients, which is linked to immune suppression, results in an initial response rate, these responses are typically of limited duration. Combining immunotherapeutic drugs with kinase-targeted agents is an attractive strategy to increase clinical efficacy. Evidence suggesting that mitogen-activated protein kinase pathway activation in tumor cells contributes to immune suppression suggests that the two approaches may be synergistic, provided that BRAF(V600E) inhibitors are nontoxic to immune cells. To assess effects of mutant BRAF inhibition on systemic immunity, we studied 13 patients with tumors carrying a BRAF mutation who underwent treatment with GSK2118436, a V600 mutant BRAF-specific inhibitor. We carried out peripheral blood immunomonitoring before and following one or two 28-day cycles of treatment. GSK2118436 treatment had no detectable impact on most immune parameters tested, including serum cytokine levels, peripheral blood cell counts, leukocyte subset frequencies, and memory CD4(+) and CD8(+) T-cell recall responses. A slight increase in serum TNF-α over the course of treatment was observed. In addition, three of the four human leukocyte antigen-A2-positive patients experienced a modest increase in circulating tumor antigen-specific CD8(+) T cells following BRAF(V600) inhibitor therapy. GSK2118436 treatment results in no detectable negative impact on existing systemic immunity or the de novo generation of tumor-specific T cells. These findings suggest that future trials combining specific BRAF(V600E) inhibition with immunotherapy should not impair immune response.