What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.