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Lung Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Tumor development is associated with the generation of an immunosuppressive tumor milieu, and therefore, consideration of the influence of multiple cell types, extracellular matrix, and metabolic mediators becomes important. Each of these components potentially represents a hurdle to T cells and their antitumor immune responses, which may also specifically be influenced by immunotherapy. Strategies to influence the tumor microenvironment are expanding and include the use of metabolic mediators such as epacadostat. In addition, adoptive T cell therapies are becoming increasingly relevant in clinical practice. Chimeric antigen receptors (CARs) are engineered antigen receptor proteins consisting of an antigen-binding region and T cell receptor (TCR) signaling domains. With this technology, T cells are genetically modified to express CARs, expanded ex vivo, and adoptively transferred to patients, acting to redirect T cells’ effector functions upon binding to antigens on tumor cells. There are a number of trials being developed in lung cancer with these technologies.
Nivolumab in squamous cell carcinoma of the head and neck
Published in Expert Review of Anticancer Therapy, 2018
Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that induces immune tolerance by T cell suppression. Epacadostat is a potent, selective oral IDO1 inhibitor. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study evaluating Epacadostat plus pembrolizumab in multiple tumor types, including HNSCC patients who received >1 prior chemotherapy regimen including a platinum agent. The combination was well tolerated and the maximum-tolerated dose (MTD) was not exceeded at epacadostat 300 mg BID and pembrolizumab 2 mg/kg or 200 mg flat dose every 3 weeks. Epacadostat 200 mg BID and pembrolizumab 200 mg flat dose were selected for the phase 2 expansion cohort. ORR was 34% for patients who received <3 prior regimens and 14% in patients who received >3 prior treatments [43].
A patent review of IDO1 inhibitors for cancer
Published in Expert Opinion on Therapeutic Patents, 2018
Jae Eun Cheong, Anil Ekkati, Lijun Sun
The clinical candidate epacadostat (18) is the quintessential example of a large number of IDO1 inhibitors containing the hydoxyamidine moiety (Figure 4). Epacadostat was first described in WO2010005958 [41] and further specified for its synthetic process in WO2015070007 [42] and dosing regimen in WO2017079669 [43]. Epacadostat inhibited human IDO1 activity in enzymatic (IC50 = 72 nM) and cellular assay (IC50 = 125 nM) of human whole blood [44]. It is developed by Incyte, and currently the most advanced IDO1 inhibitor. As a component of combination regimens together with PD-1/L1 immune checkpoint inhibitors, epacadostat is in Phase III clinical trials for patients with melanoma, lung, kidney, and head and neck cancers.
Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
Published in OncoImmunology, 2021
Jeong Hun Kim, Won Suk Lee, Hye Jin Lee, Hannah Yang, Seung Joon Lee, So Jung Kong, Soyeon Je, Hyun-Jin Yang, Jongsun Jung, Jaekyung Cheon, Beodeul Kang, Hong Jae Chon, Chan Kim
Therefore, extensive efforts have been devoted to develop a selective and potent inhibitor of the Kyn signaling pathway, leading to the development of the IDO-selective inhibitor, epacadostat.10,19,31 Epacadostat acts as a competitive inhibitor of IDO and it effectively suppresses intratumoral Kyn levels, restores anti-tumor immunity, and synergizes with ICIs in preclinical studies.32,33 Based on the encouraging preclinical results, a large Phase III trial (ECHO-301/KEYNOTE-252) was conducted where epacadostat was combined with the anti-PD-1 antibody, pembrolizumab, in patients with advanced melanoma.34,35 However, the addition of epacadostat did not prolong the overall survival compared with pembrolizumab monotherapy.36