Indoleamine Dioxygenase Inhibitors: Clinical Rationale and Current Development
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Purpose of Review
This review focuses on the recent clinical development of indolamine-2,3-dioxygenase-1 (IDO-1) inhibitors.
IDO-1 alters tryptophan metabolism in a manner enhancing T-regulatory cell activity, but pre-clinical data show that its role in tumorigenesis is context-dependent on host and tumor interaction, highlighting some challenges in understanding the molecular oncology of this enzymatic drug target. Because results from phase I/II trials of IDO-1 inhibitor monotherapy have been disappointing, current clinical trials employ IDO-1 inhibitors in combination strategies with other immunotherapy agents or with chemotherapy ± radiation. Combinations with anti-PD-1/PD-L1 antibodies are already showing promise, and related strategies are under active evaluation.
While further research is needed to elucidate the precise role of IDO-1 in tumor development, its mechanisms of action appear sufficiently distinct from other immunotherapy targets to warrant inclusion in combination immunotherapy regimens, an approach where multiple clinical trials are currently underway.
KeywordsImmune checkpoint blockade Immuno-oncology Combination therapy Epacadostat Indoximod BMS-986205
This work was supported by grants from the Canadian Cancer Society and the Liddy Shriver Sarcoma Initiative.
Compliance with Ethical Standards
Conflict of Interest
Mayanne M.T. Zhu declares that she has no conflict of interest.
Amanda R. Dancsok declares that she has no conflict of interest.
Torsten O. Nielsen has received research funding through a grant from Novartis; has received compensation as well as non-financial support from NanoString Technologies, Inc., for service as a consultant; has received compensation from Epizyme for service as a consultant; and has a patent (PAM50 breast cancer subtype and prognostic signature) issued, licensed to NanoString Technologies, and receives royalties, although this is not directly related to the submitted work.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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