Evaluation of the Immunologic Impact of RAF Inhibitors to Guide Optimal Combination of RAF Inhibitors and Immunotherapy for the Treatment of Advanced Melanoma.

摘要

During this first year of funding, we have made the following important observations. (1) T cells activated in vitro in the presence of BRAF inhibitors demonstrate a pattern of paradoxical activation characterized by upregulation of activation markers (CD69, PD-1, ICOS) and hyperactivation of the ERK signaling pathway. (2) T cells activated in vivo in the presence of BRAF inhibitors also demonstrate a pattern of paradoxical activation demonstrated by increased T cell expansion in vivo and hyperactivation of the ERK signaling pathway. (3) T cells activated in vitro in the presence of MEK inhibitors demonstrate inhibited upregulation of activation markers (CD69, PD-1, ICOS) and inhibition of the ERK signaling pathway. (4) T cells activated in vivo in the presence of MEK inhibitors also demonstrate a pattern of diminished activation demonstrated by lower T cell expansion in vivo and inhibition of the ERK signaling pathway. These first two observations have been reported in a manuscript that has been accepted for publication in the Journal Cancer Immunology Research. In addition, we have completed the following milestones that will form the foundation for future work: (1) regulatory approval for mouse studies, (2) regulatory approval for human correlative studies and 3) expansion of the BRAF/PTEN mouse colony.