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Review
. 2022 Nov:110:102461.
doi: 10.1016/j.ctrv.2022.102461. Epub 2022 Aug 30.

Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy

Yu Fujiwara  1 , Shumei Kato  2 , Mary K Nesline  3 , Jeffrey M Conroy  3 , Paul DePietro  3 , Sarabjot Pabla  3 , Razelle Kurzrock  4
Affiliations
Free article
Review

Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy

Yu Fujiwara et al. Cancer Treat Rev. 2022 Nov.
Free article

Abstract

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. Unfortunately, the phase 3 trial of the IDO1 inhibitor epacadostat combined with the PD-1 inhibitor pembrolizumab did not show clinical benefit when compared with pembrolizumab monotherapy in patients with advanced malignant melanoma, which dampened enthusiasm for IDO inhibitors. Even so, several molecules, such as the aryl hydrocarbon receptor and tryptophan 2,3-dioxygenase, were reported as additional potential targets for the modulation of the tryptophan pathway, which might enhance clinical effectiveness. Furthermore, the combination of IDO pathway blockade with agents inhibiting other signals, such as those generated by PIK3CA mutations that may accompany IDO1 upregulation, may be a novel way to enhance activity. Importantly, IDO1 expression level varies by tumor type and among patients with the same tumor type, suggesting that patient selection based on expression levels of IDO1 may be warranted in clinical trials.

Keywords: 3-dioxygenase; Aryl hydrocarbon receptor; Immune checkpoint inhibitor; Immuno-oncology; Immunotherapy; Indoleamine 2; Precision medicine.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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