Abstract A91: BGB-283 exhibits potentials in enhancing tumor immune sensitization and lymphocyte function

Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in a variety of human malignancies. Prior studies suggested that B-RAF-targeting therapies could increase antigen expression, decrease immune suppressive factors in tumor microenvironment, and improve homing of T effector cells to the tumors. Thus, selective BRAF inhibitors were suggested to possess immunosensitization properties and could be used in combination with immunotherapies to achieve more durable disease control/response in treating BRAF V600E melanomas. BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type A-RAF, B-RAF, C-RAF and B-RAF V600E. In addition, BGB-283 has potent inhibitory activity against EGFR (Mol. Can. Ther. onlinefirst 2015; doi: 10.1158/1535-7163). BGB-283 is currently under Phase 1 clinical investigations. In the present study, BGB-283 showed significant stimulation of melanocyte-differentiation antigens and HLA-A expression in BRAF V600E melanoma cell lines. Intermediate level of BGB-283 was found to stimulate proliferation of human peripheral blood mononuclear cell (PBMC) and isolated human CD4+ and CD8+ T cells. In addition, BGB-283 potentiated IFNγ releasing from PBMCs at concentration range of 30∼300 nM. In newly developed the 3D tumor spheroid/PBMC co-culture system, BGB-283 improved PBMC function as measured by cell proliferation and IFNγ production. The presence of PBMC also enhanced the anti-proliferation activity of BGB-283 on A375 BRAF V600E mutant melanoma cells in the co-culture system. Further studies have shed light on the mechanistic underpinning of the immunomodulation effect of BGB-283 and its potential differentiation from vemurafenib. These findings support BGB-283 as a promising clinical stage antitumor drug that could potentially combine with immunotherapies by enhancing immune sensitization and T cell function. Citation Format: Xi Yuan, Mi Lian, Xiaoran Wu, Lusong Luo. BGB-283 exhibits potentials in enhancing tumor immune sensitization and lymphocyte function. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A91.