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

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Technical Report,15 Sep 2012,14 Dec 2015

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Memorial Sloan-Kettering Cancer Center New York United States

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Our hypothesis is that combination therapy with MAPK inhibitors and immunotherapy will result in more rapid and durable control of melanoma than either modality alone. This hypothesis has gained support from several recent publications.1-4 Several proposed mechanisms for enhanced anti-tumor activity have been explored including changes in regulation of PD-L1 expression on tumor cells, changes in tumor antigen expression by tumor cells and changes in immune cell infiltration of the tumor microenvironment. So far, clear studies testing the role of enhanced tumor antigen releaseantigen presentation or enhanced T cell activation have not been completed and this remains a fertile area to investigate the mechanistic basis for productive combination of targeted inhibitors and immunotherapies. In the present report, we review our findings to date and describe a pattern of paradoxical T cell activation by BRAF inhibitors that results in increased T cells up regulation of activation markers, cytokines and proliferation in vitro and in vivo. These findings represent one mechanism that may be exploited to maximize the clinical benefit of combination therapies. These finding are contrasted to our observations with MEK inhibitor treatment where T cell activation including up regulation of PD-1, ICOS, CD25, CD69 are diminished in the presence of drug. This clearly sets the stage for the upcoming experiments in mouse models of melanoma testing the combination of checkpoint blockade and BRAF or MEK inhibitors in vivo.

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