eFT508: A highly selective MNK1/2 inhibitor modulates translation enhancing anti-tumor immune response Vikas K Goel, Craig Stumpf, Rajesh K Sharma, Gregory S Parker, Jocelyn Staunton, Joan Chen, Peggy A Thompson, Gary G Chiang and Kevin R Webster eFFECTOR Therapeutics, San Diego CA
Dysregulation of translation has been implicated in diverse pathological conditions, including inflammation and cancer. MNK1 and MNK2 are distal kinases in the RAS/MAPK pathway that phosphorylate targets such as eIF4E, hnRNPA1 and PSF, which ultimately affect cap-dependent translation and stability of a select subset of mRNAs. We have designed eFT508, a potent, selective inhibitor of MNK1/2, and have used it to dissect the role of these kinases in modulating immune cell function during the anti-tumor response. In macrophages and dendritic cells, eFT508 treatment led to a dose-dependent increase in MHC-II expression, which would be predicted to enhance antigen presentation and subsequently T cell activation. Consistent with this observation, eFT508 augmented T cell proliferation in a MLR reaction carried out with macrophages while CD3/CD28-stimulated proliferation was unaffected. In primary human T cells, eFT508 blocked the production of inflammatory cytokines, such as IL-10 and TNFα, due to decreased mRNA stability, which is consistent with the MNK-dependent phosphorylation of specific RNA binding proteins such as hnRNPA1. Furthermore, eFT508 treatment also resulted in the downregulation of specific immune checkpoint proteins, including PD-1, LAG3 and TIM3, at the level of protein translation, while co-stimulatory molecules such as OX-40, 4-1BB, and CD69 were unaffected. The selective effects of eFT508 have the potential to enhance anti-tumor immune response and are differentiated from the broad effects of MEK inhibitors that target upstream in the MAPK pathway blocking T cell activation and proliferation. eFT508 is currently in multiple Phase 1/2 clinical trials as a monotherapy and in combination with an anti PD-L1 antibody.
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