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

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.

The Immunomodulator 1-Methyltryptophan Drives Tryptophan Catabolism Toward the Kynurenic Acid Branch

“…However, the indirect TRP supplementation does not sufficiently explain the results in vivo because the amount of TRP, contained in 1-MT is negligible compared to the dietary derived TRP amounts, which are positively regulated by tryptophan 2,3-dioxygenase (TDO) (mainly expressed in the liver) to maintain the homeostasis of TRP (32). It has been further described that both isomers of 1-MT mimic TRP (14,33), which may feign an amino acid oversupply and, therefore, may reduce the uptake of endogenous TRP to somatic cells resulting in increased TRP levels. Although it could not be clarified conclusively whether TRP contamination of 1-MT and/or other effects such as TRP mimetics caused the increase of TRP, the summary of results from previous studies, including the present study, indicate that it seems to be a general effect.…”

“…Indoximod is under investigation in several clinical trials (7-9) while L-1-MT or the combination of both isoforms DL-1-MT is used as IDO inhibitors in preclinical studies in vivo and in vitro (10)(11)(12). According to the reported IC 50 values of L-1-MT (120 µM) and D-1-MT (2.5 mM) in HeLa cells (13), it is currently assumed that both L-and D-1-MT are weak IDO inhibitors in vivo (14,15). Indeed, the D-isomer completely fails to inhibit the enzyme activity in inflammatory stimulated HeLa cells (9).…”

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

“…In the KP, most studies focused on IDO1 because this molecule is amenable to pharmacological intervention (19)(20)(21)(22), and a couple of specific and global IDO inhibitors [including natural compounds (17,23,24)] already entered clinical trials, mostly reporting safe application and efficacy (stable disease at best outcome) (25). Current trials are evaluating the efficacy of IDO1 inhibitors in combination with chemotherapy, radiotherapy, and other immunotherapies including cytotoxic T-lymphocyteassociated protein 4 blockade (11,22).…”

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

“…Additionally, indoximod is an oral IDO/TDO pathway inhibitor that can reverse the suppression of T cells created by IDO‐expressing DCs . IDO inhibition can block host‐mediated immunosuppression, and there is preclinical and clinical evidence supporting the use of indoximod to enhance antitumor immunity in the setting of combined chemoimmunotherapy regimens, including vaccines and immune checkpoint therapy . Indoximod is currently being evaluated in a phase I trial in combination with temozolomide for children and young adults with relapsed malignant brain tumors, including HGG, and newly diagnosed DIPG (NCT02502708).…”