State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China.
Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092, Shanghai, China.
J Exp Clin Cancer Res. 2021 Feb 8;40(1):60. doi: 10.1186/s13046-021-01847-4.
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.
吲哚胺 2,3-双加氧酶 1（IDO1）是一种单体血红素酶，催化色氨酸代谢中犬尿氨酸途径的第一步和限速步骤，在免疫和神经元功能中发挥重要作用。其在包括癌症和神经退行性疾病在内的不同病理生理过程中的意义促使过去几十年中开发了 IDO1 抑制剂。然而，潜在的首个 IDO1 抑制剂（epacadostat）与抗 PD1 抗体（pembrolizumab）联合用于晚期恶性黑色素瘤患者的 III 期临床试验的阴性结果需要更好地了解 IDO1 抑制的作用。在这篇综述中，将介绍 IDO1 抑制剂的临床开发现状，并总结 epacadostat 的关键临床前和临床数据。此外，基于从 epacadostat 的临床研究结果中获得的警示性注释，将讨论用于鉴定可靠的预测生物标志物和药效标志物以及选择用 IDO1 抑制剂治疗的肿瘤类型的策略。
