Trametinib Selectively Inhibits Alloreactivity While Sparing Virus-Specific T Cells

We have previously shown that inhibition of the MEK pathway with selumetinib greatly reduced T cell proliferation induced by allo-DC stimulation with minimal loss in virus-specific cytokine production in EBV and CMV-stimulated T cells in vitro, and that selumetinib significantly reduced GVHD and increased survival in a GVHD mouse model.   Thus, MEK inhibitors represent a novel class of immunosuppressive agents that potentially target GVHD initiation while sparing beneficial immunity in the allo-SCT setting.  We sought to determine if trametinib, a recently FDA-approved MEK inhibitor based on clinical responses in the melanoma setting, would also demonstrate selective inhibition of alloreactivity while preserving virus-specific immune function.  In 6 allo-DC/responder PBMC pairs, we assessed the dose response of inhibition of proliferation by trametinib, and found similar dose response patterns to selumetinib with ~50% inhibition of alloreactivity at the 1 μM dose and nearly complete inhibition at 10 μM (Figure 1).   As previously reported with selumetinib, the percentage of polyfunctional CMV and EBV-stimulated PBMC capable of producing IL-2, IFN-γ, TNF-α or MIP1-β was unchanged by exposure to MEK inhibition (n=4, CMV pp65 peptide responses shown in Figure 2). While the overall fraction of functional responding cells to virus did not change in response to MEK inhibition, TNF-α production was reduced at higher doses of both trametinib and selumetinib.   Further experiments are planned, both in vitro and in animal models, to confirm the potential utility of this class of drugs to reduce GVHD while preserving virus-specific T cell function in the allo-SCT setting.