The MEK Inhibitior Trametinib Selectively Suppresses Gvhd, While Sparing GVT Effects

BACKGROUND AND OBJECTIVE: Antineoplastic MEK inhibitors have immunomodulatory activity. MEK inhibition selectively suppresses naïve/central memory T cells while sparing effector memory T cells, and delays the onset of murine GVHD (Shindo, Kim, Komanduri et al. Blood 2013). We investigated whether MEK inhibition selectively suppresses GVHD in additional murine BMT models, and whether Graft-versus-Tumor (GVT) effects are spared. METHODS: We adopted three murine BMT models: 1) Transplantation of B6-BM and T cells into B6D2F1 mice (MHC-haploidentical BDF1 model); 2) Transplantation of B10.D2-BM and T cells into Balb/c mice (Skin GVHD and immune alopecia model); 3) Transfusion of P815 cells in the BDF1 model (GVT model). Various doses of the MEK inhibitor trametinib (or vehicle) were orally given. RESULTS: 15-days administration of Trametinib significantly prolonged survival of GVHD mice (Fig. 1), and suppressed GVHD symptoms and pathology in the gut and skin. BDF1-GVHD mice revealed increased phosphorylation of ERK in peripheral blood CD4 and CD8 T cells, which was suppressed by trametinib (Fig. 2). Trametinib also suppressed expansion and functional differentiation of donor T cells in vivo. Although high-dose trametinib (1.0 mg/kg/day) exerted toxicity, low-dose trametinib (0.1-0.3 mg/kg/day) was tolerable while still suppressing GVHD. Notably, in the GVT model, trametinib did not shorten survival of P815- and T cell-transplanted mice, indicating that it does not suppress GVT effects (Fig. 3). Furthermore, trametinib therapy did not interfere with engraftment nor expansion of Foxp3⁺ regulatory T cells (data not shown). CONCLUSIONS: These results confirmed that trametinib selectively suppresses GVHD-inducing T cells while sparing tumor-specific T cells and other cell subsets in vivo. Given the demonstrated safety of trametinib in clinical trials of melanoma, MEK inhibition may be a promising candidate for translational studies aimed at preventing or treating GVHD after allogeneic transplantation.