IDO: A Target for Cancer Treatment

Beverly E Barton, PhD

Uncategorized

Immune checkpoints modulate immune responses by providing signals that attenuate T cells. The importance of immune checkpoints in cancer treatment has been underscored by recently approved therapies. For example, ipilimumab is a monoclonal antibody directed against the cytotoxic T-lymphocyte antigen (CTLA)-4. Normally, CTLA-4 would prevent the costimulatory activity of CD80 or CD86 (on antigen-presenting cells), which bind to CD28 expressed on T cells; removing CTLA-4 immunosuppressive activity allows costimulatory activity to continue, culminating in antitumor cytolytic T-cell activity.¹ Ipilimumab is approved for the treatment of advanced melanoma. Thus, targeting immune checkpoints is an active area of research for new cancer therapies.

Indoleamine ^2,3-dioxygenase (IDO), an enzyme found in both tumors and tumor-infiltrating cells, performs the first step of tryptophan catabolism: the conversion of L-tryptophan to N-formylkynurenine. Most human tumors constitutively express this enzyme,² and samples from breast cancer tissue revealed that IDO was highly expressed in malignant but not in benign samples.³ In a study by Ino and colleagues, more than 50% of gynecologic cancer cases were found to have high IDO expression, and the level of IDO expression correlated with the surgical stage and patient outcomes.⁴ In other studies, overexpression of IDO promoted metastasis of ovarian cancer,⁵ and mice bearing IDO-deficient glioblastomas survived significantly longer than mice bearing IDO-expressing tumors.6 Furthermore, in a mouse model of melanoma, the novel IDO inhibitor INCB23843 showed control of tumor growth, which was mediated by CD8+ T cells that produce interleukin (IL)-2.⁷ Overall, these data indicate a strong role for IDO as a target for cancer therapy.

It has been noted for years that IDO is induced under immunosuppressive conditions, such as the activation of signal transducer and activator of transcription (STAT) 3 or ligation of CTLA-4.^8-10 Recently, it was revealed that constitutive IDO expression may be sustained by autocrine signaling through a loop involving activated STAT3.11 In vivo experiments demonstrated that the draining lymph nodes of tumor-bearing mice contained IDO-positive dendritic cells. Although these dendritic cells comprised only 0.5% of the total dendritic cell population, they suppressed T-cell responses to tumor antigens and to unrelated antigens.12 Adding indoximod, the D isomer of 1-methyl-tryptophan, abrogated IDO-mediated suppression and restored T-cell functions.¹² Therefore, IDO is an immune checkpoint with activity in cancer immunity, one that can be inhibited appropriately for therapeutic gains. This review will discuss IDO as an immune checkpoint and describe the most recent clinical trials under way with IDO inhibitors.

Immune Checkpoints and Their Role in Cancer Progression
Immune checkpoints are inhibitory pathways that are important for maintaining self-tolerance and dampening the duration and amplitudes of immune responses to foreign antigens¹³; such checkpoints are essential to prevent the development of autoimmunity. However, checkpoints also dampen antitumor immunity.¹⁴ Several mechanisms by which immune checkpoints function have been elucidated thus far, including inhibitory T-cell pathways, regulatory immune cells, and metabolic enzymes, such as IDO.¹⁴

One mechanism already familiar to oncologists is CTLA-4, which binds to T-cell–expressed CD28 and inhibits the required costimulatory interaction with either CD80 or CD86 on antigen-presenting cells.^1,15 CTLA-4 is expressed by CD8+ and CD4+ T cells; thus, CTLA-4 suppresses cytotoxic and helper T-cell functions.¹³ Overall, CTLA-4 provides the opposite signal to CD80 or CD86 that CD28 would need to activate T-cell responses. In the absence of a second signal, T cells become anergic. CTLA-4 was the first immune checkpoint for successful targeting in cancer therapy; however, it benefits only a subset of patients with melanoma.¹⁶

The anti–CTLA-4 monoclonal antibody ipilimumab proved useful for the treatment of melanoma and is approved for treating advanced disease; another anti–CTLA-4 monoclonal antibody, tremelimumab, is in current clinical trials.¹ In one study, ipilimumab responders and nonresponders were grouped by serum vascular endothelial growth factor (VEGF) levels. Patients with VEGF levels of >43 pg/mL were significantly less likely to respond to ipilimumab treatment.¹⁷ Such success and questions lead investigators to search for other immune checkpoints, the inhibition of which may prove to be therapeutic targets for cancer. Among the immune checkpoints under active investigation for cancer treatment is IDO.

IDO in Cancer: A Potential New Treatment Target
IDO comprises 2 isozymes, IDO-1 and IDO-2. Genetic polymorphisms affecting the function for the genes of both isozymes have been described.¹⁸ IDO catalyzes the first step in tryptophan catabolism to acetyl coenzyme A: (the conversion of L-tryptophan to N-formylkynurenine.¹⁹ In the liver, this step is catalyzed by the related enzyme tryptophan ^2,3-dioxygenase, which is a separate area of investigation as a potential cancer target.²⁰

Although both isoforms are expressed by tumor cells, there is evidence suggesting that IDO-1 is more important than IDO-2 as an immune checkpoint.²¹ Nevertheless, there is evidence showing that IDO-2 may also be impor­tant in regulating immune responses to tumors and in the pathogenesis of rheumatoid arthritis; in addition, studies have found that indoximod inhibits IDO-2 preferentially over IDO-1.^22,23 The biology of IDO is under active investigation.²⁴ For the purpose of this review, IDO will be used to mean either isoform. Where one isoform is targeted by a particular agent or is expressed preferentially by cells or tissue, that isoform will be specified.

IDO plays a role in dampening otherwise deleterious immune responses, such as preventing the rejection of a fetus as an allograft during pregnancy.^9,25 Early experiments with fetal allografts showed that IDO was expressed by suppressive macrophages, and the competitive inhibitor 1-methyl tryptophan abrogated the suppression^25,26; female mice of 1 inbred strain given 1-methyl tryptophan, then mated with males of a histoincompatible strain, lost all their concepti.²⁵

IDO is a major gene product that is induced in mature dendritic cells by the action of interferon-?.²⁷ IL-6, produced when the CD²⁸ signal is short-circuited (eg, by a CD²⁸ immunoglobulin construct), in turn induces IDO expression and concomitant immune suppression, which is STAT3 mediated. Silencing endogenous STAT3 (by inhibiting the suppressor of cytokine signaling 3) abrogates IDO expression.⁸ Plasmacytoid dendritic cells in draining lymph nodes express IDO. When the antigen is used in grafted tumor cells, IDO-expressing dendritic cells render T cells anergic to the tumors and even to unrelated nontumor antigens; the suppression could be overcome when 1-methyl tryptophan is given to mice.¹²

Only a small proportion (approximately 0.5%) of dendritic cells in the draining lymph nodes need to express IDO to abrogate T-cell–mediated responses, which testifies to the potent immunosuppressive effects of IDO.^10,12 The converse is also true: defective tryptophan catabolism may result in autoimmunity; for example, in nonobese diabetic mice, IDO modified by peroxynitrites failed to function normally. Furthermore, interferon-? failed to induce IDO in nonobese diabetic mice.²⁸ Inhibiting peroxynitrite restored IDO function and tolerance in the nonobese diabetic mice.²⁸

In cancer, there are several paths to sustained IDO expression. One such path is an autocrine loop involving IL-6, aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor that responds to planar aryl hydrocarbons), and STAT3. AHR responds to hydrocarbons such as benzo(a)pyrene, and is believed to be part of the carcinogenic process of aryl hydrocarbons.¹¹ AHR also binds kynurenine, a product of IDO action, and induces IL-6.¹¹ Whereas IL-6–induced STAT3 plays a role in IDO induction, it alone is not sufficient. However, once kynurenine is produced, IDO expression in tumor cells is sustained through an AHR–IL-6–STAT3–IDO autocrine loop.¹¹

An alternate route to sustained IDO expression was discovered in c-Myc–transformed mouse keratinocytes. In these cells, which may serve as model cells for other c-Myc–transformed tumor types, IDO was under the control of Bin1, a gene whose expression is decreased in many human cancers and which interacts with the Myc gene product.²⁹ Investigators found that loss of Bin1 expression elevated STAT1-dependent and NF-?B–dependent expression of IDO, thereby allowing the tumors to escape T-cell–dependent antitumor immunity.²⁹ The same investigators observed that inhibiting IDO with 1-methyl tryptophan in a murine virus breast cancer model overcame the effect of loss of Bin1 expression. Furthermore, 1-methyl tryptophan enhanced the effects of conventional chemotherapeutic agents, such as cisplatin, cyclophosphamide, doxorubicin, and paclitaxel.²⁹

Mechanisms of IDO-Mediated Immune Escape
Evidence suggests several pathways by which IDO mediates escape from antitumor immunity. Depletion of tryptophan and accumulation of kynurenine metabolites appear to affect immune function. Several kynurenine metabolites have been shown to be immunomodulatory, especially 3-hydroxyanthranilic acid.^30,31 Local production of kynurenine metabolites is required to attenuate inflammation in models of chronic granulomatous disease.³²

In the absence of tumors, IDO appears to control aspects of innate immunity and inflammation.³³ Specifically, chimeric mice infected with Mycobacterium tuberculosis but unable to express interferon-? in their bone marrow were unable to induce IDO, and subsequently overexpressed the Th17 cytokine IL-17.³⁴ Moreover, the authors observed that the products of IDO catabolism inhibited IL-17 via inhibition of IL-23.³⁴ It is interesting to note that IDO is not required for self-tolerance; mice lacking IDO or treated long-term with IDO inhibitors do not develop spontaneous autoimmunity.³³ The effects of IDO are most manifest in acquired peripheral tolerance, such as the maternal acquired tolerance to a fetus as allograft, as discussed above.²⁵

IDO-mediated suppression of the mammalian target of rapamycin (mTOR) complex 1 in T cells is another mechanism of IDO-mediated escape from antitumor immunity.³⁵ This was demonstrated in experiments that also revealed that the addition of 1-methyl tryptophan relieved the inhibition of mTOR and protein kinase C (PKC)-?, demonstrating the potential use of mTOR complex 1 and PKC-? as pharmacodynamic biomarkers for anti-IDO activity or anti-IDO responses in patients with cancer.³⁶

The mechanism by which the mTOR complex or PKC-? receives signals generated by tryptophan catabolism is under investigation. Evidence suggests that low tryptophan levels may inhibit mTOR.³⁷ Low tryptophan levels trigger the expression of stress-responsive kinase general control nonderepressible (GCN) 2.^37,38 An increase in uncharged transfer RNA levels induces the kinase activity of GCN2,³⁹ thereby initiating the downstream signaling pathway. Mice lacking GCN2 are resistant to the immunomodulatory effects of IDO.³⁷

Kynurenine, kynurenine metabolites, and tryptophan depletion may directly inhibit effector T-cell activation, proliferation, and survival.³³ In addition, IDO action helps to create, activate, and maintain regulatory T cells. Naive CD4+ T cells in an IDO-active environment often become Foxp3-positive–inducible regulatory T cells.^40-43 Moreover, IDO activity on regulatory T cells prevents their reprogramming to inflammatory or helper T-cell phenotypes, thereby maintaining their suppressive phenotype.^44-46 IDO-activated regulatory T cells in the draining lymph nodes of tumor-bearing mice contribute to tumor-induced tolerance and escape from immunity.⁴⁷ Cells expressing IDO in the draining lymph nodes had plasmacytoid dendritic cell morphology, and similar cells were found in the draining lymph nodes of patients with melanoma.^47,48

Some insight into the mechanism of IDO’s effects––beyond its function as a checkpoint in cancer immunity––may be gleaned from its effects in cancer therapy. As described above, the IDO inhibitor 1-methyl tryptophan synergized with conventional chemotherapeutic agents such as paclitaxel in a mouse breast cancer model.²⁹ Recently, it was found that IDO mediated resistance to the poly-ADP ribose polymerase inhibitor olaparib; antisense to IDO restored the effects of olaparib.⁴⁹ The authors suggested a previously unrecognized role for IDO in DNA repair mediated by the poly-ADP ribose polymerase inhibitor.⁴⁹ In a spontaneous mouse model of gastrointestinal stromal tumors, imatinib activated CD8+ T cells and induced apoptosis of regulatory T cells by reducing IDO expression in tumor cells.^35,50 Specimens from patients with gastrointestinal stromal tumors revealed a close correlation between imatinib sensitivity in the tumor-infiltrating T cells and IDO expression.⁵⁰ The authors then showed that imatinib reduced IDO levels through the inhibition of KIT signaling.⁵⁰ These observations imply that IDO may have activities related to cancer progression that are in addition to its immune checkpoint activity. Further research in this area is certainly warranted.

Recent Clinical Trials with IDO Inhibitors Indoximod, NLG-919, and INCB024360
Several IDO inhibitors are in development for use in cancer or autoimmune diseases. Overall, 4 compounds that are in preclinical development (ie, TX-2274, UTX-2, UTX-3, and UTX-4) are conjugates of unsubstituted L-tryptophan. Unlike TX-2274 and UTX-4, which are competitive inhibitors, UTX-2 and UTX-3 bind the enzyme-substrate complex; these IDO inhibitors have Ki (inhibitory constant) ranging from >15 µM to <440 µM.51 No biological effects of these inhibitors, in vitro or in vivo, have been published, although they are designed to target hypoxia as well as IDO through the tirapazamine moiety of the conjugate.⁵¹ The use of siRNA (small interfering RNA) to disrupt immune suppression by silencing IDO is also being studied.⁵² In vivo results demonstrated that silencing IDO with siRNA inhibited tumor growth and significantly postponed tumor formation time by enhancing previously suppressed antitumor T-cell responses.⁵²

Compounds in clinical development—indoximod, INCB024360, and NLG919—are orally active drugs in trials for various types of solid tumors. Indoximod has been used extensively in the in vitro and animal-based experiments described above and is currently in phase 2 trials. In one trial, it is being used in conjunction with an adenovirus vaccine Ad.p53 DC for solid metastatic tumors; patient enrollment for this trial has completed.⁵³ In a previous study, the Ad.p53 DC vaccine overexpressed p53 when it was introduced into dendritic cells and resulted in tumor rejection.⁵⁴ In another phase 2 trial, indoximod plus docetaxel will be used to treat metastatic breast cancer⁵⁵; the study calls for 154 patients to enroll. A combined phase 1/2 trial will examine indoximod plus temozolomide for primary brain tumors⁵⁶; patient recruitment has not yet completed. The combination treatment with indoximod plus ipilimumab will be studied in a phase 1/2 trial for stage III or IV melanoma; the phase 1 portion will enroll 12 patients, and the phase 2 portion will enroll up to 80 patients.⁵⁷ A phase 2 trial involving patients with castration-resistant prostate cancer will determine if indoximod added to sipuleucel-T augments the immune responses enhanced by sipuleucel-T^58,59; 50 patients are expected to enroll.

Preliminary results have been published for the phase 1/2 trial of the IDO inhibitor INCB024360 for metastatic melanoma.⁶⁰ Preliminary analysis showed that 6 of 8 patients had smaller tumors at their first evaluation, and the confirmed disease control rate was 75%.⁶¹ Enrollment in this trial is complete, and final study results are anticipated in August 2014.

NLG919 is being assessed in a phase 1 trial of patients with refractory advanced solid tumors; up to 36 patients will be enrolled, and final data will be collected in 2015.⁶²

Conclusions
IDO is an important checkpoint in cancer immunity. Gene knockout, antisense, and silencing experiments provided evidence that inhibiting IDO is beneficial for cancer treatment. Overall, 3 IDO inhibitors, indoximod, INCB024360, and NLG919, are in current clinical trials. Results of these trials are eagerly anticipated.

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