UCLA

Targeted therapies like vemurafenib and dabrafenib that block oncogenic BRAF result in high response rates and improved overall survival in patients with melanoma. However, the response has limited durability and most tumors relapse. On the contrary, immunotherapy for melanoma results in low response rates that tend to be extremely durable. We hypothesized that combining immunotherapy with BRAF inhibitors and other targeted therapies being developed for melanoma may improve the anti-tumor effects by combining the benefits of both modes of therapy. To test this hypothesis, we developed a BRAFV600E-driven murine model of melanoma, SM1, that is syngeneic to immunocompetent mice. Combined treatment of vemurafenib plus adoptive cell transfer (ACT) immunotherapy demonstrated superior anti-tumor effect compared with single treatments alone in SM1. However, SM1 is an aggressive model in which the tumor bearing mice have to be sacrificed within two to three weeks, and this combination therapy did not lead to sustained tumor responses. We noticed that SM1 secreted colony stimulating factor-1 (CSF-1) that recruits immune suppressive tumor infiltrating myeloid cells (TIMs) including macrophages and myeloid derived suppressor cells (MDSC). We hypothesized that blocking CSF-1 receptor (CSF-1R) with a small molecule tyrosine kinase inhibitors such as PLX3397, as it would inhibit immune suppressive TIMs and synergize with immunotherapy. Combination of PLX3397 and ACT induced superior anti-tumor effect and PLX3397 increased number of tumor infiltrating lymphocytes (TILs) and IFN-gamma; production in T-cells by depleting TIMs. Based on the results of these two studies, we then combined PLX3397 and vemurafenib in the SM1 model and the combination mediated superior anti-tumor response. The macrophage inhibitory effects of PLX3397 treatment and paradoxical activation of immune cells with wild type BRAF mediated by vemurafenib resulted in more TILs with increased IFN-γ production. Taken together, we provide support for the testing of immunotherapy, BRAF, and CSF-1R inhibitors combinations in patients with BRAFV600 mutant metastatic melanoma.