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Review
. 2018 Sep 11:8:370.
doi: 10.3389/fonc.2018.00370. eCollection 2018.

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

Eric Fox  1 , Thomas Oliver  1 , Melissa Rowe  1 , Sunil Thomas  2 , Yousef Zakharia  3 , Paul B Gilman  1   2 , Alexander J Muller  2   4 , George C Prendergast  2   4
Affiliations
Review

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

Eric Fox et al. Front Oncol. .

Abstract

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

Keywords: Immunotherapy; immune adjuvant; immuno-chemotherapy; immuno-radiotherapy; immunometabolism.

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Figures

Figure 1
Figure 1
Sites of indoximod action in cancer. IDO1, TDO, and IDO2 are expressed variously in malignant, immune, stromal and vascular cells in the tumor microenvironment and in antigen-presenting cells (APC) of tumor-draining lymph nodes. TDO and IDO2 are relatively more narrowly expressed than IDO1 in human cancers, with TDO overexpressed in some tumors independently or in parallel with IDO1 and IDO2 expressed in antigen-presenting cells including B cells where it may influence IDO1 function (28). Tryptophan catabolism in tumor cells leads to locoregional generation of kynurenine at the cost of tryptophan, enabling suppression of local T effector cells (Teff), licensing and recruitment of myeloid-derived suppressor cells (MDSC) and support of a tumor-enabling vasculature. The tumor microenvironment variously recruits cancer-associated fibroblasts, vascular endothelial and inflammatory myeloid cells that express IDO1 and/or IDO2. Tumor antigens absorbed by IDO1/IDO2-expressing antigen-presenting cells (APC) rove to draining lymph nodes where they promote the formation and activation of T regulatory cells (Tregs). Studies suggest that indoximod enables Teff in tumors and attenuate in draining lymph nodes, in the latter case by acting on dendritic cells leading to suppression and/or reprogramming of Tregs and the formation of Th17-expressing T helper cells.
Figure 2
Figure 2
Indoximod mechanisms of action. Tryptophan catabolism proceeds through pathways leading to serotonin or NAD production, the latter through the kynurenine pathway which handles ~95% of Trp catabolism in mammals. Indoximod is a Trp mimetic which mTORC1 interprets as L-Trp under conditions of high Trp catabolism and autophagy. Thus, the drug acts to block the suppressive signal on mTORC1 function generated by IDO/TDO activity. Other suggested mechanisms of action include an indirect suppression of IDO2 activity; a modulation of kynurenine-regulated AHR function, which may also influence feedback on IDO1 expression and activity; and an influence on gut microbial physiology influencing systemic immunity (see the text).
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