June 2014, Part 2
IDO: A Target for Cancer TreatmentUncategorized
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-cellâ€“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 antiâ€“CTLA-4 monoclonal antibody ipilimumab proved useful for the treatment of melanoma and is approved for treating advanced disease; another antiâ€“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 imporÂtant 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 suppression25,26; 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-cellâ€“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-6â€“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 AHRâ€“IL-6â€“STAT3â€“IDO autocrine loop.11
An alternate route to sustained IDO expression was discovered in c-Mycâ€“transformed mouse keratinocytes. In these cells, which may serve as model cells for other c-Mycâ€“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-?Bâ€“dependent expression of IDO, thereby allowing the tumors to escape T-cellâ€“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-positiveâ€“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 IDOâ€™s effectsâ€“â€“beyond its function as a checkpoint in cancer immunityâ€“â€“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 ÂµM to <440 ÂµM.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 developmentâ€”indoximod, INCB024360, and NLG919â€”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-T58,59; 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
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.
1. Ascierto PA, Marincola FM, Ribas A. Anti-CTLA4 monoclonal antibodies: the past and the future in clinical application. J Transl Med. 2011;9:196.
2. Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269-1274.
3. Isla Larrain MT, Rabassa ME, Lacunza E, et al. IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis. Tumour Biol. 2014 Apr 1. Epub ahead of print.
4. Ino K, Tanizaki Y, Kobayashi A, Toujima S, Mabuchi Y, Minami S. Role of the immune tolerance-inducing molecule indoleamine 2,3-dioxygenase in gynecologic cancers. J Cancer Sci Ther. 2012;S13.
5. Tanizaki Y, Kobayashi A, Toujima S, et al. Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer via inducing immunosuppressive environment. Cancer Sci. 2014 May 14. Epub ahead of print.
6. Wainwright DA, Chang AL, Dey M, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014 Apr 1. Epub ahead of print.
7. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.
8. Orabona C, Belladonna ML, Vacca C, et al. Cutting edge: silencing suppressor of cytokine signaling 3 expression in dendritic cells turns CD28-Ig from immune adjuvant to suppressant. J Immunol. 2005;174:6582-6586.
9. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4:762-774.
10. Baban B, Hansen AM, Chandler PR, et al. A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation. Int Immunol. 2005;17:909-919.
11. Litzenburger UM, Opitz CA, Sahm F, et al. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget. 2014;5:1038-1051.
12. Munn DH, Sharma MD, Hou D, et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest. 2004;114:280-290.
13. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.
14. Andersen MH. The targeting of immunosuppressive mechanisms in hematological malignancies. Leukemia. 2014 Mar 18. Epub ahead of print.
15. Callahan MK, Wolchok JD, Allison JP. Antiâ€“CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol. 2010;37:473-484.
16. Hanks BA, Holtzhausen A, Evans K, Heid M, Blobe GC. Combinatorial TGF-? signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma. J Clin Oncol. 2014;32(suppl):3011.
17. Yuan J, Zhou J, Dong Z, et al. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res. 2014;2:127-132.
18. Arefayene M, Philips S, Cao D, et al. Identification of genetic variants in the human indoleamine 2,3-dioxygenase (IDO1) gene, which have altered enzyme activity. Pharmacogenet Genomics. 2009;19:464-476.
19. Lehninger AL. Biochemistry. The Molecular Basis of Cell Structure and Function. 2nd ed. New York, NY: Worth Publishers, Inc; 1975.
20. Pantouris G, Mowat CG. Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase. Biochemical and biophysical research communications. Biochem Biophys Res Commun. 2014;443:28-31.
21. LĂ¶b S, KĂ¶nigsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58:153-157.
22. Metz R, DuHadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound d-1-methyl-tryptophan. Cancer Res. 2007;67:7082-7087.
23. Merlo LMF, Pigott E, DuHadaway JB, et al. IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J Immunol. 2014;192:2082-2090.
24. Lob S, Konigsrainer A, Rammensee H-G, Opelz G, Terness P. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer. 2009;9:445-452.
25. Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191-1193.
26. Cady SG, Sono M. 1-methyl-dl-tryptophan, ?-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and ?-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch Biochem Biophys. 1991;291:326-333.
27. Barton BE. STAT3: a potential therapeutic target in dendritic cells for the induction of transplant tolerance. Expert Opin Ther Targets. 2006;10:459-470.
28. Grohmann U, Fallarino F, Bianchi R, et al. A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J Exp Med. 2003;198:153-160.
29. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11:312-319.
30. Belladonna ML, Orabona C, Grohmann U, Puccetti P. TGF-? and kynurenines as the key to infectious tolerance. Trends Mol Med. 2009;15:41-49.
31. Favre D, Mold J, Hunt PW, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010;2:32ra36.
32. Romani L, Fallarino F, De Luca A, et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature. 2008;451:211-215.
33. Munn DH. Blocking IDO activity to enhance anti-tumor immunity. Front BioÂsci (Elite Ed). 2012;4:734-745.
34. Desvignes L, Ernst JD. Interferon-?-responsive nonhematopoietic cells regulate the immune response to mycobacterium tuberculosis. Immunity. 2009;3:974-985.
35. Prendergast GC, Smith C, Thomas S, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 2014;63:721-735.
36. Metz R, Rust S, DuHadaway JB, et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl- tryptophan. OncoImmunology. 2012;1:1460-1468.
37. Munn DH, Sharma MD, Baban B, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633-642.
38. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007;117:1147-1154.
39. Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol Cell. 2000;6:269-279.
40. Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immu nol. 2006;176:6752-6761.
41. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181:5396-5404.
42. Manches O, Munn D, Fallahi A, et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest. 2008;118:3431-3439.
43. Chung DJ, Rossi M, Romano E, et al. Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood. 2009;114:555-563.
44. Sharma MD, Hou DY, Liu Y, et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 2009; 113:6102-6111.
45. Baban B, Chandler PR, Sharma MD, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009;183:2475-2483.
46. Sharma MD, Hou DY, Baban B, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity. 2010;33:942-954.
47. Sharma MD, Baban B, Chandler P, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3- dioxygenase. J Clin Invest. 2007;117:2570-2582.
48. Lee JR, Dalton RR, Messina JL, et al. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab Invest. 2003;83:1457-1466.
49. Vareki SM, Rytelewski M, Figueredo R, et al. Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin. Oncotarget. 2014;5:2778-2791.
50. Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17:1094-1100.
51. Nakashima H, Ikkyu K, Nakashima K, et al. Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety. Adv Exp Med Biol. 2010;662:415-421.
52. Zheng X, Koropatnick J, Li M, et al. Reinstalling antitumor immunity by inhibiting tumor-derived immunosuppressive molecule IDO through RNA interference. J Immunol. 2006;177:5639-5646.
53. Soliman HH, Minton SE, Ismail-Khan R, et al. A phase 2 study of Ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors. J Clin Oncol. 2014; 32(suppl):Abstract TPS3125.
54. Nikitina EY, Chada S, Muro-Cacho C, et al. An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53. Gene Ther. 2002;9:345-352.
55. Soliman HH, Minton SE, Ismail-Khan R, et al. A phase 2 study of docetaxel in combination with indoximod in metastatic breast cancer. J Clin Oncol. 2014;32(suppl): Abstract TPS3124.
56. Zakharia Y, Johnson TS, Colman H, et al. A phase I/II study of the combination of indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors. J Clin Oncol. 2014;32(suppl):Abstract TPS2107.
57. Kennedy E, Rossi GR, Vahanian NN, Link CJ. Phase 1/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus ipilimumab for the treatment of unresectable stage 3 or 4 melanoma. J Clin Oncol. 2014;32(suppl):Abstract TPS9117.
58. Jha GG, Miller JS. A randomized, double-blind phase 2 study of sipuleucel-T followed by indoximod or placebo in the treatment of patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32(suppl):Abstract TPS5111.
59. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
60. Liu X, Shin N, Koblish HK, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010;115:3520-3530.
61. Gibney GT, Hamid O, Gangadhar TC, et al. Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma. J Clin Oncol. 2014;32(suppl):Abstract 3010.
62. Khleif S, Munn D, Nyak-Kapoor A, et al. First-in-human phase 1 study of the novel indoleamine-2,3-dioxygenase (IDO) inhibitor NLG-919. J Clin Oncol. 2014; 32(suppl):Abstract TPS3121.
Nivolumab, a Novel Antiâ€“PD-1 Monoclonal Antibody for the Treatment of Solid and Hematologic Malignancies
Immunotherapy for the treatment of cancer has been an active area of research, with the recent approval of ipilimumab (Yervoy) in 2011. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), a cell surface molecule expressed solely on T cells required for self-tolerance. The rationale for blocking an immune blockade such as CTLA-4 [ Read More ]
With the recent advancements in the treatment of patients with metastatic melanoma, in particular with immunomodulating therapies, the development of unique immune-related side effects has posed novel management challenges. The first drug in this class to receive FDA approval for the treatment of unresectable stage III or IV melanoma is [ Read More ]