Epacadostat

Marching into the second decade after the approval of ipilimumab, it is clear that immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of melanoma. Although the current edge is already high, with a 4-year OS% of 77.9% for adjuvant nivolumab and a 6.5-year OS% of 49% for nivolumab/ipilimumab combination in the metastatic setting, a high proportion of patients with advanced melanoma have no benefit from immunotherapy, or experience an early disease relapse/progression in the first few months of treatment, surviving much less...

INTRODUCTION: Indoleamine 2,3-dioxygenase 1 (IDO1) is highly related to the immune evasion of a wide range of malignancies due to its role in the immune suppression caused by the depletion of tryptophan (Trp) and the accumulation of kynurenine (Kyn). The combination of IDO1 inhibitors with other treatments represents a promising strategy in immunotherapy, although considerable challenges lie ahead. AREAS COVERED: This review focuses on patent publications searched from Espacenet and Google Scholar, and related to IDO1 inhibitors with potential anti-cancer utilization during the period 2018-2022...

BACKGROUND: Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS: The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS: The most common treatment-related adverse events were fatigue (30...

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Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer-associated depression. Behavioral tests (open field, forced swim, tail suspension) and biochemical assays (LC-MS metabolomics) were utilized to characterize a depressive-phenotype in tumor-bearing mice (relative to non-tumor-bearing mice)...

Introduction: Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse. Materials: To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment...

BACKGROUND: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine...

Cancer immunotherapy has shifted the paradigm for cancer treatment in the past decade, but new immunotherapies enabling the effective treatment of solid tumors are still greatly demanded. Here we report a pore-forming hydrogel-based immunotherapy that enables simultaneous recruitment of dendritic cells and in situ activation of T cells, for reshaping the immunosuppressive tumor microenvironment and amplifying cytotoxic T lymphocyte response. The injectable pore-forming hydrogel composed of porogen-dispersed alginate network can form a macroporous structure upon injection into mice, and enables controlled release of granulocyte-macrophage colony-stimulating factor (GM-CSF), a chemoattractant for recruiting dendritic cells, and epacadostat, an inhibitor of indoleamine 2, 3-dioxygenase for activating T cells...

Strategies for unlocking immunosuppression in the tumor microenvironment have been investigated to overcome resistance to first-generation immune checkpoint blockade with anti- programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agents. Indoleamine 2,3-dioxygenase (IDO) 1, an enzyme catabolizing tryptophan to kynurenine, creates an immunosuppressive environment in preclinical studies. Early phase clinical trials investigating inhibition of IDO1, especially together with checkpoint blockade, provided promising results...

Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide...

Background: Tryptophan catabolism leading to T cell suppression mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of tumor immune escape, and IDO1 inhibitors have attracted increasing attention as anticancer therapeutics. However, the phase III clinical trial (ECHO-301/KEYNOTE-252) of epacadostat (INCB024360) had disappointing outcomes. This revealed that purification of IDO1 with high purity is one of the major constraints that limit the development of its inhibitors...

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the kynurenine (Kyn) pathway of tryptophan metabolism in the first step, and the kynurenine pathway plays a fundamental role in immunosuppression in the tumor microenvironment. Therefore, researchers are vigorously developing IDO1 inhibitors, hoping to apply them to cancer immunotherapy. Nowadays, there have been 11 kinds of IDO1 inhibitors entering clinical trials, among which many inhibitors have shown good tumor inhibitory effect in phase I/II clinical trials...

Researchers have pinpointed metabolic alterations that may allow tumors to evade the IDO1 inhibitor epacadostat. Tumor cells enlisted an alternative pathway to break down tryptophan, the target of IDO1, and increased the activity of pathways that generate NAD+. The metabolic changes also suppressed CD8+ T cells.

Background: Immune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients benefit from these costly therapies. Therefore, there is an unmet need to better understand the effect of ICIs on immune effector cells. This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4+ , and CD8+ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells...

PURPOSE: Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors. EXPERIMENTAL DESIGN: We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies...

Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactory clinical efficacies of selective IDO1 inhibitors have impeded their further development, suggesting that they do not exert sufficient antitumor effects by selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed in some human tumors, and emerging evidence suggests that concomitant inhibition of IDO1/2 may have synergistic effects in cancer treatment, revealing a promising cancer immunotherapeutic strategy...

S-epacadostat is an efficient and selective small-molecule inhibitor of indoleamine 2,3-dioxygenase 1. It is an epacadostat analog with a sulfur atom instead of a nitrogen atom at the furazan C3 position. The present study documents the pharmacokinetics of S-epacadostat in dogs and its metabolic pathway. After oral administration of 15 mg/kg of S-epacadostat in dogs, the time to peak concentrations was 0.80 h, the mean elimination half-life was 7.3 h, and the absolute bioavailability was 55.8%. Furthermore, we identified S-epacadostat metabolites in dog plasma and dog liver microsomes by UPLC-Q Exactive Orbitrap HRMS...

The deficiency of antigen-specific T cells and the induction of various treatment-induced immunosuppressions still limits the clinical benefit of cancer immunotherapy. Although the chemo-immunotherapy adjuvanted with Toll-like receptor 7/8 agonist (TLR 7/8a) induces immunogenic cell death (ICD) and in situ vaccination effect, indoleamine 2,3-dioxygenase (IDO) is also significantly increased in the tumor microenvironment (TME) and tumor-draining lymph node (TDLN), which offsets the activated antitumor immunity...

BACKGROUND: One of the important metabolic pathways in cancer progression is tryptophan catabolism by the indoleamin-2,3-dioxygenase (IDO) enzyme, which suppresses the immune system and induces tolerance. Inhibition of IDO1 is an important therapeutic goal for immunotherapy in many cancers such as metastatic melanoma. Epacadostat (EPA) is a very strong inhibitor of IDO1, and its clinical studies are being performed in a higher clinical phase than other inhibitors. In this study, we have developed a new liposomal EPA formulation to reduce the dose, side effects, and treatment costs...

BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aim to use a mouse model to elucidate the immune related molecular mechanisms of hepatitis, one of the common ICI irAEs. METHODS: Immune phenotyping and molecular profiling were performed on PD1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor, epacadostat, or a 4-1BB agonist antibody...