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What Is the Prospect of Indoleamine 2,3-Dioxygenase 1 Inhibition in Cancer?

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What Is the Prospect of Indoleamine 2,3-Dioxygenase 1 Inhibition in Cancer? Yao et al. Journal of Experimental & Clinical Cancer Research (2021) 40:60 https://doi.org/10.1186/s13046-021-01847-4 REVIEW Open Access What is the prospect of indoleamine 2,3- dioxygenase 1 inhibition in cancer? Extrapolation from the past Yu Yao1†, Heng Liang1†, Xin Fang1, Shengnan Zhang1, Zikang Xing1, Lei Shi1, Chunxiang Kuang2, Barbara Seliger3 and Qing Yang1* Abstract Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed. Keywords: Indoleamine 2,3-dioxygenase 1, Indoleamine 2,3-dioxygenase 1 inhibitor, Epacadostat, Tryptophan 2,3- dioxygenase, Cancer immunotherapy, Immune checkpoint Background immunity mediated by blocking immune inhibitory With increasing recognition of evading immunological pathways and/or inhibitory cells in the tumor micro- destruction as a hallmark of cancer acquired during its environment (TME) or enhancing the specificity of anti- development[1], immunotherapy has emerged as a novel tumor immunity by inducing the expansion of T cells and important pillar of cancer treatment in addition to and antibodies directed to well-defined tumor anti- surgery, radiation, chemotherapy, and targeted therapy. gens[2]. The launch of immune checkpoint inhibitors Instead of directly killing cancer cells or suppressing the (ICPIs) including the first cytotoxic T-lymphocyte anti- abnormal signal transduction within cancers, cancer im- gen 4 (CTLA-4) blocking antibody ipilimumab in munotherapy aims to leverage the patient’s immune sys- 2011[3] and programmed death receptor 1 or ligand 1 tem to eliminate tumor cells by enhancing tumor (PD-1/PD-L1) blocking antibodies pembrolizumab and nivolumab in 2014[4, 5] represents the substantive pro- gress in the field and boosts immunotherapy as a new * Correspondence: [email protected] † standard therapy for many cancer types. To date, the US Yu Yao and Heng Liang contributed equally to this manuscript. 1State Key Laboratory of Genetic Engineering, Department of Biochemistry, Food and Drug Administration has approved the use of School of Life Sciences, Fudan University, Songhu Road 2005, 200438 PD-1/PD-L1 and CTLA-4 targeted therapies for the Shanghai, China treatment of more than 15 cancers including melanoma, Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yao et al. Journal of Experimental & Clinical Cancer Research (2021) 40:60 Page 2 of 14 non-small cell lung cancer (NSCLC), small cell lung can- caused spontaneous immune rejection of allogeneic fe- cer, squamous cell carcinoma of the head and neck, tuses[24]. Later, the IDO1-mediated immune tolerance renal cell carcinoma (RCC), hepatocellular carcinoma in tumors has been noted, experimental models suggest (HCC), classical Hodgkin lymphoma, urothelial carcin- that IDO1 expression prevents rejection of tumor cells oma, colorectal cancer (CRC) and other cancer types[3– in immunogenic mice[25–30]. The imbalances in the 5]. However, limited response due to innate and ac- level of TRP and KYN as well as the overexpression of quired resistance as well as serious adverse effects espe- IDO1 have been reported in many cancers[25–29, 31– cially life-threatening immune-related toxicities of anti- 47]. High IDO1 expression was associated with a de- CTLA-4 and anti-PD-1/PD-L1 antibodies call for a need creased survival[48] and the extent of IDO1 overexpres- to identify other immunotherapy options targeting dif- sion depends on the tumor type and risk factors[49]. ferent mechanisms of immunosuppression in tumors Three downstream effector pathways, including the gen- that could be used alone or in combination with existing eral control nonderepressible 2 (GCN2), mammalian tar- treatments. Currently over three thousand drugs direct- get of rapamycin (mTOR), and aryl hydrocarbon ing against more than four hundred active targets are receptor (AhR) pathways, have been implicated in the being investigated under different stages from preclinical biological responses to IDO1-mediated TRP depletion or to post-approval[6]. In this context indoleamine 2,3- KYN accumulation. In addition, some studies have dioxygenase 1 (IDO1) is one of the most studied target shown that these effector pathways mediate immuno- of cancer immunotherapies by virtue of its effects on im- suppression in the TME[50–53]. TRP depletion pro- mune suppression in the TME[6]. motes the accumulation of uncharged tRNA, resulting in IDO1, a monomeric heme-containing enzyme, is one a GCN2-dependent inhibition of protein synthesis that of the three enzymes that catalyze the first and rate- is accompanied by cell cycle arrest and irresponsiveness limiting step in the kynurenine pathway (KP), leading to to immunological challenges[54]. TRP depletion leads to the degradation of the essential amino acid tryptophan inhibition of the immunoregulatory kinases mTOR and (TRP) and generation of kynurenine (KYN) and other protein kinase C, along with the induction of autoph- downstream metabolites, in addition to tryptophan 2,3- agy[55]. KYN accumulation promotes the translocation dioxygenase (TDO) and indoleamine 2,3-dioxygenase 2 of AhR from the cytosol to nucleus, where it binds target (IDO2)[7, 8]. TRP is required for protein synthesis and genes and activates their transcription, inducing tolero- TRP metabolites can act as neurotransmitters and sig- genic immune responses with the consequent benefit to nalling molecules. Thus, TRP and its metabolites play tumor progression and migration[53, 56]. The exact con- important roles in diverse physiological processes ran- tribution of each effector function to tumor immuno- ging from cell growth and survival to the coordination suppression remains to be determined. And it is likely of responses to internal and external environmental that each pathway counts for much or less in different changes[9]. IDO1 is expressed in various tissues, organs tumors although all of them cooperate synergistically in and cell types, catalyzing the conversion of a wide range the development of immunosuppression in the TME. of substrates including TRP and 5- Based on these data, the inhibition of IDO1 has become hydroxytryptamine[10, 11]. TDO mainly exists in the an exciting approach as cancer immunotherapy and liver and brain[12, 13], specifically catalyzing the conver- IDO1 inhibitors have been intensively investigated dur- sion of TRP and some of its derivatives substituted in ing the recent years. Multiple IDO1 inhibitors with dif- the 5- and 6-positions of the indole ring[14, 15]. TDO is ferent structural skeleton have been developed[57– thought to be the main modulator of TRP catabolism 67] and some have entered clinical development and is responsible for regulating systemic TRP levels[16], (Table 1). However, the further development of IDO1 while IDO1 plays an important role in TRP catabolism inhibitors has experienced a significant setback due to under pathological conditions[17, 18]. The host- the recent failure of the phase III trial (ECHO-301/KEY- protective effect of IDO1 in parasitic infection has been NOTE-252) of epacadostat (INCB024360), the would-be first discovered in 1990s, which is attributable to a re- first-in-class IDO1 inhibitor, which had been anticipated duced availability of TRP in the inflammatory environ- to receive regulatory approval on the basis of promising ment[19, 20]. In addition, as many KP metabolites are results from initial studies (Fig. 1)[24,
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