Targeting MNK1/2 with eFT508: Modulating Immune Checkpoints and Cytokines for Enhanced Anti-Tumor Response

The dysregulation of mRNA translation is linked to the development of various cancers. MNK1 and MNK2 proteins, which are involved in several cancer and immune pathways, can influence the stability and translation of specific mRNAs that are crucial for tumor growth and immune responses by phosphorylating proteins like eIF4E, hnRNPA1, and PSF. eFT508, a selective inhibitor of MNK1 and MNK2, has been shown to regulate the translation and stability of genes involved in inflammation, stress response, and anti-tumor immunity through ribosome profiling.

In vitro studies on human immune cells have indicated that eFT508 does not negatively impact IL-2 production, T cell proliferation, or viability. It does, however, selectively reduce the induction of IL-10 and certain immune checkpoint receptors such as PD-1 and LAG3. LAG3 mRNA has been found to be sensitive to eFT508 due to specific elements in its 5'-UTR, and IL-10 mRNA is destabilized by eFT508 treatment, leading to decreased IL-10 production in activated T cells.

Furthermore, eFT508 has been observed to increase the expression of MHC class II molecules on tumor cells and antigen-presenting cells through an IL-10/MARCH1 dependent mechanism. In vivo studies using the CT26 BALB/C syngeneic tumor model have shown that while eFT508 does not affect tumor cell proliferation in vitro, it exhibits significant anti-tumor activity in vivo, alters tumor-infiltrating lymphocytes, and helps establish immune memory. The combination of eFT508 with anti-PD-1 or anti-PD-L1 antibodies has demonstrated enhanced efficacy and increased responder rates.

eFT508 is currently being evaluated in phase I/II clinical trials for patients with advanced solid tumors and lymphoma. The research suggests that eFT508, in combination with checkpoint blockade, warrants further investigation for its potential in promoting anti-tumor immunity.