Trial watch: IDO inhibitors in cancer therapy.
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Journal: 2017/February - OncoImmunology
ISSN: 2162-4011
Abstract:
Indoleamine 2,3-dioxigenase 1 (IDO1) is the main enzyme that catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", i.e., the metabolic cascade that converts the essential amino acid L-tryptophan (Trp) into L-kynurenine (Kyn). IDO1, which is expressed constitutively by some tissues and in an inducible manner by specific subsets of antigen-presenting cells, has been shown to play a role in the establishment and maintenance of peripheral tolerance. At least in part, this reflects the capacity of IDO1 to restrict the microenvironmental availability of Trp and to favor the accumulation of Kyn and some of its derivatives. Also, several neoplastic lesions express IDO1, providing them with a means to evade anticancer immunosurveillance. This consideration has driven the development of several IDO1 inhibitors, some of which (including 1-methyltryptophan) have nowadays entered clinical evaluation. In animal tumor models, the inhibition of IDO1 by chemical or genetic interventions is indeed associated with the (re)activation of therapeutically relevant anticancer immune responses. This said, several immunotherapeutic regimens exert robust clinical activity in spite of their ability to promote the expression of IDO1. Moreover, 1-methyltryptophan has recently been shown to exert IDO1-independent immunostimulatory effects. Here, we summarize the preclinical and clinical studies testing the antineoplastic activity of IDO1-targeting interventions.
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Oncoimmunology 3(10): e957994
PMID: 25941578

Trial watch: IDO inhibitors in cancer therapy

Gustave Roussy Cancer Campus; Villejuif, France
INSERM U1138; Paris, France
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France;
Université Paris-Sud/Paris XI; Orsay, Paris, France
Equipe 13; Centre de Recherche des Cordeliers; Paris, France
Université Pierre et Marie Curie/Paris VI; Paris, France
Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
INSERM U970; Paris, France
Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France
NewLink Genetics Co.; Ames, IA USA
Department of Neurooncology; University Hospital Heidelberg and National Center for Tumor Diseases; Heidelberg, Germany
German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology; German Cancer Research Center (DKFZ); Heidelberg, Germany
INSERM U1015; CICBT507; Villejuif, France
Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus; Villejuif, France
These authors equally contributed to this work.
These authors share senior co-authorship.
Correspondence to: Guido Kroemer; Email: rf.egnaro@remeork; Lorenzo Galluzzi; Email: ti.enofadov@codaed
Received 2014 Aug 20; Accepted 2014 Aug 21.
Copyright © 2014 Taylor & Francis Group, LLC

Abstract

Indoleamine 2,3-dioxigenase 1 (IDO1) is the main enzyme that catalyzes the first, rate-limiting step of the so-called “kynurenine pathway”, i.e., the metabolic cascade that converts the essential amino acid L-tryptophan (Trp) into L-kynurenine (Kyn). IDO1, which is expressed constitutively by some tissues and in an inducible manner by specific subsets of antigen-presenting cells, has been shown to play a role in the establishment and maintenance of peripheral tolerance. At least in part, this reflects the capacity of IDO1 to restrict the microenvironmental availability of Trp and to favor the accumulation of Kyn and some of its derivatives. Also, several neoplastic lesions express IDO1, providing them with a means to evade anticancer immunosurveillance. This consideration has driven the development of several IDO1 inhibitors, some of which (including 1-methyltryptophan) have nowadays entered clinical evaluation. In animal tumor models, the inhibition of IDO1 by chemical or genetic interventions is indeed associated with the (re)activation of therapeutically relevant anticancer immune responses. This said, several immunotherapeutic regimens exert robust clinical activity in spite of their ability to promote the expression of IDO1. Moreover, 1-methyltryptophan has recently been shown to exert IDO1-independent immunostimulatory effects. Here, we summarize the preclinical and clinical studies testing the antineoplastic activity of IDO1-targeting interventions.

Keywords: 1-methyl-D-tryptophan, INCB024360, indoximod, interferon γ, NLG919, peptide-based anticancer vaccines
Abbreviations: AHR, aryl hydrocarbon receptor; BIN1, bridging integrator 1; CTLA4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cell; FDA, Food and Drug Administration; GCN2, general control non-derepressible 2; HCC, hepatocellular carcinoma; IDO, indoleamine 2,3-dioxigenase; IFNγ, interferon γ; Kyn, L-kynurenine; NK, natural killer; ODN, oligodeoxynucleotide; TDO2, tryptophan 2,3-dioxigenase; TLR, Toll-like receptor; Treg, regulatory T cell; Trp, L-tryptophan
Abstract

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