1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Cancer Biology
  4. Volume 4, 2020
  5. Article

Annual Review of Cancer Biology

Volume 4, 2020

Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma?

Abstract

Indoleamine-2,3 dioxygenase 1 (IDO1) contributes to tumor immunosuppression by enzymatically degrading tryptophan, which is required for T cell activity, and producing kynurenine. Small-molecule inhibitors, such as epacadostat, have been developed to block IDO1 activity. In preclinical models, they can restore antitumoral T cell immunity and synergize with immune checkpoint inhibitors or cancer vaccines. Based on encouraging clinical results in early phase trials, a randomized phase III study (ECHO-301/KN-252) was launched in metastatic melanoma to test the benefit of adding epacadostat to the reference pembrolizumab therapy. The result was negative. We briefly review the clinical trials that investigated epacadostat in cancer patients and discuss possible explanations for this negative result. We end by suggesting paths to resume clinical development of compounds targeting the IDO1 pathway, which in our view remains an attractive target for cancer immunotherapy.

Keyword(s): epacadostat, IDO1 inhibitor, immunosuppression, indoleamine-2,3 dioxygenase, melanoma, pembrolizumab
Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030419-033635
2020-03-04
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/4/1/annurev-cancerbio-030419-033635.html?itemId=/content/journals/10.1146/annurev-cancerbio-030419-033635&mimeType=html&fmt=ahah

Literature Cited

  1. Albini E, Rosini V, Gargaro M, Mondanelli G, Belladonna ML et al. 2017. Distinct roles of immunoreceptor tyrosine-based motifs in immunosuppressive indoleamine 2,3-dioxygenase 1. J. Cell. Mol. Med. 21:165–76
     [Google Scholar]
  2. Beatty GL, O'Dwyer PJ, Clark J, Shi JG, Bowman KJ et al. 2017. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin. Cancer Res. 23:3269–76
     [Google Scholar]
  3. Blair AB, Kleponis J, Thomas DL 2nd, Muth ST, Murphy AG et al. 2019. IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma. J. Clin. Investig. 129:1742–55
     [Google Scholar]
  4. Cancer Genome Atlas Res. Netw. Weinstein JN, Collisson EA, Mills GB, Shaw KR et al. 2013. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45:1113–20
     [Google Scholar]
  5. Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D et al. 2009. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. PNAS 106:12055–60
     [Google Scholar]
  6. Comin-Anduix B, Escuin-Ordinas H, Ibarrondo FJ 2016. Tremelimumab: research and clinical development. OncoTargets Ther 9:1767–76
     [Google Scholar]
  7. Daud A, Saleh MN, Hu J, Bleeker JS, Riese MJ et al. 2018. Epacadostat plus nivolumab for advanced melanoma: updated phase 2 results of the ECHO-204 study. J. Clin. Oncol. 36:9511 Abstr .)
     [Google Scholar]
  8. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR et al. 2006. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176:6752–61
     [Google Scholar]
  9. Fatokun AA, Hunt NH, Ball HJ 2013. Indoleamine 2,3-dioxygenase 2 (IDO2) and the kynurenine pathway: characteristics and potential roles in health and disease. Amino Acids 45:1319–29
     [Google Scholar]
  10. Gibney GT, Hamid O, Lutzky J, Olszanski AJ, Mitchell TC et al. 2019. Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. J. Immunother. Cancer 7:80
     [Google Scholar]
  11. Gutierrez-Vazquez C, Quintana FJ. 2018. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48:19–33
     [Google Scholar]
  12. Hennequart M, Pilotte L, Cane S, Hoffmann D, Stroobant V et al. 2017. Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance. Cancer Immunol. Res. 5:695–709
     [Google Scholar]
  13. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363:711–23
     [Google Scholar]
  14. Hoffmann D, Dvorakova T, Stroobant V, Solvay M, Klaessens S et al. 2020. Tryptophan 2,3-dioxygenase expression identified in intratumoral pericytes of most human cancers and in tumor cells of hepatocarcinoma. Cancer Immunol. Res. http://www.doi.org/10.1158/2326-6066.CIR-19-0040
    [Crossref] [Google Scholar]
  15. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP 2013. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210:1389–402
     [Google Scholar]
  16. Hoos A. 2016. Development of immuno-oncology drugs—from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15:235–47
     [Google Scholar]
  17. Jacquelot N, Roberti MP, Enot DP, Rusakiewicz S, Ternes N et al. 2017. Predictors of responses to immune checkpoint blockade in advanced melanoma. Nat. Commun. 8:592
     [Google Scholar]
  18. Jusof FF, Bakmiwewa SM, Weiser S, Too LK, Metz R et al. 2017. Investigation of the tissue distribution and physiological roles of indoleamine 2,3-dioxygenase-2. Int. J. Tryptophan Res. 10: https://doi.org/10.1177/1178646917735098
    [Crossref] [Google Scholar]
  19. Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S et al. 2009. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol. Brain 2:8
     [Google Scholar]
  20. Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL et al. 2010. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol. Cancer Ther. 9:489–98
     [Google Scholar]
  21. Lemos H, Huang L, Prendergast GC, Mellor AL 2019. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat. Rev. Cancer 19:162–75
     [Google Scholar]
  22. Lewis-Ballester A, Forouhar F, Kim SM, Lew S, Wang Y et al. 2016. Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. Sci. Rep. 6:35169
     [Google Scholar]
  23. Liu M, Wang X, Wang L, Ma X, Gong Z et al. 2018. Targeting the IDO1 pathway in cancer: from bench to bedside. J. Hematol. Oncol. 11:100
     [Google Scholar]
  24. Liu X, Shin N, Koblish HK, Yang G, Wang Q et al. 2010. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115:3520–30
     [Google Scholar]
  25. Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C et al. 2018a. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J. Clin. Oncol. 36:108 Abstr .)
     [Google Scholar]
  26. Long GV, Schachter J, Ribas A, Arance AM, Grob JJ et al. 2018b. 4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006. J. Clin. Oncol. 36:9503 Abstr .)
     [Google Scholar]
  27. Luke JJ, Gelmon K, Pachynski RK, Desai J, Moreno V et al. 2017. Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers. J. Immunother. Cancer 5:Suppl. 3O41 Abstr .)
     [Google Scholar]
  28. Madonna G, Ballesteros-Merino C, Feng Z, Bifulco C, Capone M et al. 2018. PD-L1 expression with immune-infiltrate evaluation and outcome prediction in melanoma patients treated with ipilimumab. Oncoimmunology 7:e1405206
     [Google Scholar]
  29. Mellor AL, Lemos H, Huang L 2017. Indoleamine 2,3-dioxygenase and tolerance: Where are we now?. Front. Immunol. 8:1360
     [Google Scholar]
  30. Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC 2007. 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 67:7082–87
     [Google Scholar]
  31. Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH et al. 2012. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology 1:1460–68
     [Google Scholar]
  32. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA 2010. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185:3190–98
     [Google Scholar]
  33. Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS et al. 2018. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol. 36:3223–30
     [Google Scholar]
  34. Mondal A, Smith C, DuHadaway JB, Sutanto-Ward E, Prendergast GC et al. 2016. IDO1 is an integral mediator of inflammatory neovascularization. EBioMedicine 14:74–82
     [Google Scholar]
  35. Moyer BJ, Rojas IY, Murray IA, Lee S, Hazlett HF et al. 2017. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. Toxicol. Appl. Pharmacol. 323:74–80
     [Google Scholar]
  36. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC 2005. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11:312–19
     [Google Scholar]
  37. Muller AJ, Manfredi MG, Zakharia Y, Prendergast GC 2019. Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin. Immunopathol. 41:41–48
     [Google Scholar]
  38. Munn DH, Mellor AL. 2016. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 37:193–207
     [Google Scholar]
  39. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y et al. 2005. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–42
     [Google Scholar]
  40. Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS et al. 2002. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297:1867–70
     [Google Scholar]
  41. Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW et al. 2016. PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology 5:e1235107
     [Google Scholar]
  42. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I et al. 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203
     [Google Scholar]
  43. Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML et al. 2011. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol. 12:870–78
     [Google Scholar]
  44. Pantouris G, Serys M, Yuasa HJ, Ball HJ, Mowat CG 2014. Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1. Amino Acids 46:2155–63
     [Google Scholar]
  45. Perez RP, Riese MJ, Lewis KD, Saleh MN, Daud A et al. 2017. Epacadostat plus nivolumab in patients with advanced solid tumors: preliminary phase I/II results of ECHO-204. J. Clin. Oncol. 35:3003 Abstr .)
     [Google Scholar]
  46. Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E et al. 2012. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. PNAS 109:2497–502
     [Google Scholar]
  47. Platten M, Nollen EAA, Rohrig UF, Fallarino F, Opitz CA 2019. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat. Rev. Drug Discov. 18:379–401
     [Google Scholar]
  48. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K et al. 2015. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372:2006–17
     [Google Scholar]
  49. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF et al. 2008. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71
     [Google Scholar]
  50. Reardon DA, Desjardins A, Rixe O, Cloughesy T, Alekar S et al. 2017. ATIM-29. A phase 1 study of PF-06840003, an oral indole 2,3-dioxygenase 1 (IDO1) inhibitor in patients with malignant gliomas. Neuro-Oncology 19:Suppl. 6 vi32 (Abstr.)
    [Google Scholar]
  51. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J 2013. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368:1365–66
     [Google Scholar]
  52. Robert C, Long GV, Brady B, Dutriaux C, Maio M et al. 2015. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372:320–30
     [Google Scholar]
  53. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J et al. 2011. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364:2517–26
     [Google Scholar]
  54. Schramme F, Crosignani S, Frederix K, Hoffmann D, Pilotte L et al. 2020. Inhibition of tryptophan-dioxygenase activity increases the anti-tumor efficacy of immune checkpoint inhibitors. Cancer Immunol. ResIn press. http://www.doi.org/10.1158/2326-6066.CIR-19-0041
     [Crossref] [Google Scholar]
  55. Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB et al. 2012. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2:722–35
     [Google Scholar]
  56. Sonner JK, Deumelandt K, Ott M, Thome CM, Rauschenbach KJ et al. 2016. The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas. Oncoimmunology 5:e1240858
     [Google Scholar]
  57. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF 2014. 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 2:3
     [Google Scholar]
  58. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y et al. 2013. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5:200ra116
     [Google Scholar]
  59. Taube JM, Young GD, McMiller TL, Chen S, Salas JT et al. 2015. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin. Cancer Res. 21:3969–76
     [Google Scholar]
  60. Terness P, Bauer TM, Rose L, Dufter C, Watzlik A et al. 2002. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J. Exp. Med. 196:447–57
     [Google Scholar]
  61. Theate I, van Baren N, Pilotte L, Moulin P, Larrieu P et al. 2015. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol. Res. 3:161–72
     [Google Scholar]
  62. Triplett TA, Garrison KC, Marshall N, Donkor M, Blazeck J et al. 2018. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36:758–64
     [Google Scholar]
  63. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D et al. 2003. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9:1269–74
     [Google Scholar]
  64. van Baren N, Van den Eynde BJ 2015a. Tryptophan-degrading enzymes in tumoral immune resistance. Front. Immunol. 6:34
     [Google Scholar]
  65. van Baren N, Van den Eynde BJ 2015b. Tumoral immune resistance mediated by enzymes that degrade tryptophan. Cancer Immunol. Res. 3:978–85
     [Google Scholar]
  66. Yu CP, Fu SF, Chen X, Ye J, Ye Y et al. 2018. The clinicopathological and prognostic significance of IDO1 expression in human solid tumors: evidence from a systematic review and meta-analysis. Cell. Physiol. Biochem. 49:134–43
     [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030419-033635
Loading
Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma?
Annual Review of Cancer Biology 4, 241 (2020); https://doi.org/10.1146/annurev-cancerbio-030419-033635
/content/journals/10.1146/annurev-cancerbio-030419-033635
/content/journals/10.1146/annurev-cancerbio-030419-033635
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error