Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Immunotherapy

Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes

Subjects

Abstract

Immune checkpoint inhibitors, as single-agent therapy, have shown modest clinical efficacy in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). As has been successfully shown in other less immunogenic hematologic malignancies, rationally designed combination approaches may be more effective than single-agent checkpoint inhibitors, and may be the approach to pursue in AML/MDS. Hypomethylating agents (HMAs) such as azacitidine, while enhancing anti-tumor immune response, concurrently dampen immune response by upregulating inhibitory immune checkpoint molecule expression. Immune checkpoint molecule upregulation may be an important mechanism of azacitidine resistance. These findings have resulted in multiple clinical trials combining HMAs with immune checkpoint blockade. Clinical trial data have shown encouraging response rates and durable responses without resorting to stem cell transplant. In this review, we discuss preclinical data supporting the use of these agents in combination, and focus on clinical and correlative data emerging from numerous clinical trials investigating HMA-immune checkpoint inhibitor combinations in AML/MDS.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

    CAS  Article  Google Scholar 

  2. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.

    Article  Google Scholar 

  3. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.

    CAS  Article  Google Scholar 

  4. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–17.

    CAS  Article  Google Scholar 

  5. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    CAS  Article  Google Scholar 

  6. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    CAS  Article  Google Scholar 

  7. Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. Immune modulation in cancer with antibodies. Annu Rev Med. 2014;65:185–202.

    CAS  Article  Google Scholar 

  8. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268–77.

    CAS  Article  Google Scholar 

  9. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O’Donnell E, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin. Cancer Res. 2012;18:1611–8.

    CAS  Article  Google Scholar 

  10. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  Google Scholar 

  11. Moskowitz C, Ribrag V, Michot JM, Martinelli G, Zinzani PL, Gutierrez M, et al. (editors). PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical hodgkin lymphoma after brentuximab vedotin failure: Preliminary results from a phase 1b study (KEYNOTE-013). 56th ASH Annual Meeting and Exposition. San Francisco, CA; 2014.

  12. Diefenbach CS, H F, David KA, et al. A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory hodgkin lymphoma: A trial of the ECOG-ACRIN Cancer Research Group (E4412 Arms D and E). Blood. 2016;128:1106.

    Google Scholar 

  13. Falchi L, Sawas A, Deng C, Amengual JE, Colbourn DS, Lichtenstein E, et al. Rate of complete metabolic responses to immune checkpoint inhibitors in extremely heavily pre-treated patients with classical Hodgkin’s lymphoma and immunoepigenetic priming. J Clin Oncol. 2016;34(15_suppl):e19012–e.

    Article  Google Scholar 

  14. Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, et al. Safety & tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130:267–70.

    CAS  Article  Google Scholar 

  15. Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017;129:3071–3.

    CAS  Article  Google Scholar 

  16. Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129:2437–42.

    CAS  Article  Google Scholar 

  17. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51.

    CAS  Article  Google Scholar 

  18. Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15:69–77.

    CAS  Article  Google Scholar 

  19. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-hodgkin’s lymphoma: Safety and efficacy of re-treatment. J Clin Oncol. 2000;18:3135–43.

    CAS  Article  Google Scholar 

  20. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: Preliminary results of a phase Ib study. J Clin Oncol. 2016;34:2698–704.

    CAS  Article  Google Scholar 

  21. Vincent Ribrag DEA, Martinelli G, DJ Green, T Wise-Draper, JG Posada, Vij R, et al. Pembrolizumab monotherapy for relapsed/refractory multiple myeloma (rrmm): Phase 1b keynote-013 study. EHA. 23 Jun 2017;181631;2017.

  22. San Miguel J, Mateos M, Shah JJ, Ocio EM, Rodriguez-Otero P, Reece D, et al. (editors). Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Keynote-023. American Society of Hematology Annual Meeting; 57th annual meeting, Orlando, Florida 2015.

  23. Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, et al. Pembrolizumab, pomalidomide and low dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;130:1189–97.

    CAS  Article  Google Scholar 

  24. San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055–66.

    Article  Google Scholar 

  25. Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128:497–503.

    CAS  Article  Google Scholar 

  26. FDA alerts healthcare professionals and oncology clinical investigators about two clinical trials on hold evaluating KEYTRUDA® (pembrolizumab) in patients with multiple myeloma [press release]; 2017. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm.

  27. FDA halts multiple immunotherapy trials [press release]; 2017. http://www.ajpb.com/news/fda-halts-multiple-immunotherapy-trials

  28. FDA places holds on several durvalumab combination trials [press release]; 2017. http://www.onclive.com/web-exclusives/fda-places-holds-on-several-durvalumab-combination-trials

  29. Daver N, Basu S, Garcia-Manero G, Cortes J, Ravandi F, Ning J, et al. Defining the immune checkpoint landscape in patients (pts) with acute myeloid leukemia. American Society of Hematology. Blood 2016;128:2900.

  30. Rifca Le Dieu DCT, Ramsay AG, Mitter R, Miraki-Moud F, Fatah R, Lee AM, Lister TA, et al. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood. 2009;114:3909–16.

    Article  Google Scholar 

  31. Vidriales MB, Orfao A, Lopez-Berges MC, Gonzalez M, Hernandez JM, Ciudad J, et al. Lymphoid subsets in acute myeloid leukemias: increased number of cells with NK phenotype and normal T-cell distribution. Ann Hematol. 1993;67:217–22.

    CAS  Article  Google Scholar 

  32. Van den Hove LE, Vandenberghe P, Van Gool SW, Ceuppens JL, Demuynck H, Verhoef GE, et al. Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. Leuk Res. 1998;22:175–84.

    Article  Google Scholar 

  33. Schnorfeil FM, Emmerig K, Neitz JS, Beck B, Draenert R, Hiddemann W, et al. Pseudo-exhaustion of CD8 + T cells in AML. Blood. 2013;122:2615.

    Google Scholar 

  34. Tan J, Chen S, Xu L, Lu S, Zhang Y, Chen J, et al. Increasing frequency of T cell immunosuppressive receptor expression in CD4 + and CD8 + T cells may related to T cell exhaustion and immunosuppression in patients with AML. Blood. 2016;128:5166.

    Google Scholar 

  35. Le Dieu R, Taussig DC, Ramsay AG, Mitter R, Miraki-Moud F, Fatah R, et al. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood. 2009;114:3909–16.

    Article  Google Scholar 

  36. Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005;115:1797–805.

    Article  Google Scholar 

  37. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114:1545–52.

    CAS  Article  Google Scholar 

  38. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8 + T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117:4501–10.

    CAS  Article  Google Scholar 

  39. Williams P, Basu S, Garcia-Manero G, Cortes JE, Ravandi F, Al-Hamal Z, et al. Checkpoint Expression By Acute MyeloidLeukemia (AML) and the Immune Microenvironment Suppresses Adaptive Immunity. American Society of Hematology. Abstract (617), Georgia World Congress Center, Georgia, Atlanta, USA 2016.

  40. Chen X, Liu S, Wang L, Zhang W, Ji Y, Ma X. Clinical significance of B7-H1 (PD-L1) expression in human acute leukemia. Cancer Biol Ther. 2008;7:622–7.

    CAS  Article  Google Scholar 

  41. Goltz D, Gevensleben H, Grunen S, Dietrich J, Kristiansen G, Landsberg J, et al. PD-L1 (CD274) promoter methylation predicts survival in patients with acute myeloid leukemia. Leukemia. 2017;31:738–43.

    CAS  Article  Google Scholar 

  42. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–8.

    CAS  Article  Google Scholar 

  43. Isidori A, Salvestrini V, Ciciarello M, Loscocco F, Visani G, Parisi S, et al. The role of the immunosuppressive microenvironment in acute myeloid leukemia development and treatment. Expert Rev Hematol. 2014;7:807–18.

    CAS  Article  Google Scholar 

  44. Orleans-Lindsay JK, Barber LD, Prentice HG, Lowdell MW. Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function—implications for the adoptive immunotherapy of leukaemia. Clin Exp Immunol. 2001;126:403–11.

    CAS  Article  Google Scholar 

  45. Ustun C, Miller JS, Munn DH, Weisdorf DJ, Blazar BR. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? Blood. 2011;118:5084–95.

    CAS  Article  Google Scholar 

  46. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–41.

    CAS  Article  Google Scholar 

  47. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101:3722–9.

    CAS  Article  Google Scholar 

  48. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103:4619–21.

    CAS  Article  Google Scholar 

  49. Croitoru-Lamoury J, Lamoury FM, Caristo M, Suzuki K, Walker D, Takikawa O, et al. Interferon-gamma regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoS ONE. 2011;6:e14698.

    CAS  Article  Google Scholar 

  50. Corm S, Berthon C, Imbenotte M, Biggio V, Lhermitte M, Dupont C, et al. Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients’ sera by HPLC and is inducible by IFN-gamma. Leuk Res. 2009;33:490–4.

    CAS  Article  Google Scholar 

  51. Yuan Y, Lu X, Tao CL, Chen X, Shao HW, Huang SL. Forced expression of indoleamine-2,3-dioxygenase in human umbilical cord-derived mesenchymal stem cells abolishes their anti-apoptotic effect on leukemia cell lines in vitro. Vitr Cell Dev Biol Anim. 2013;49:752–8.

    CAS  Article  Google Scholar 

  52. Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25 + T regulatory cells. Blood. 2007;109:2871–7.

    CAS  PubMed  Google Scholar 

  53. Schnorfeil FM, Lichtenegger FS, Emmerig K, Schlueter M, Neitz JS, Draenert R, et al. T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. J Hematol Oncol. 2015;8:93.

    Article  Google Scholar 

  54. Wendelbo O, Nesthus I, Sjo M, Paulsen K, Ernst P, Bruserud O. Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapy-induced leukopenia. Cancer Immunol Immunother. 2004;53:740–7.

    Article  Google Scholar 

  55. Lamble A, Kosaka Y, Huang F, Sasser K, Adams H, Tognon C, et al. Mass cytometry as a modality to identify candidates for immune checkpoint inhibitor therapy within acute myeloid leukemia. American Society of Hematology. Blood 2016;128:2829.

  56. Legat A, Speiser DE, Pircher H, Zehn D, Fuertes Marraco SA. Inhibitory receptor expression depends more dominantly on differentiation and activation than “Exhaustion” of human CD8 T cells. Front Immunol. 2013;4:455.

    Article  Google Scholar 

  57. Medyouf H, Mossner M, Jann JC, Nolte F, Raffel S, Herrmann C, et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell. 2014;14:824–37.

    CAS  Article  Google Scholar 

  58. Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, Kamiyama R. Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia. 1998;12:486–92.

    CAS  Article  Google Scholar 

  59. Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–611.

    CAS  Article  Google Scholar 

  60. Wei Y, Chen R, Dimicoli S, Bueso-Ramos C, Neuberg D, Pierce S, et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34 + cells. Leukemia. 2013;27:2177–86.

    CAS  Article  Google Scholar 

  61. Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359–65.

    CAS  Article  Google Scholar 

  62. Kotsianidis I, Bouchliou I, Nakou E, Spanoudakis E, Margaritis D, Christophoridou AV, et al. Kinetics, function and bone marrow trafficking of CD4 + CD25 + FOXP3 + regulatory T cells in myelodysplastic syndromes (MDS). Leukemia. 2009;23:510–8.

    CAS  Article  Google Scholar 

  63. Kordasti SY, Ingram W, Hayden J, Darling D, Barber L, Afzali B, et al. CD4 + CD25high Foxp3 + regulatory T cells in myelodysplastic syndrome (MDS). Blood. 2007;110:847–50.

    CAS  Article  Google Scholar 

  64. Epling-Burnette PK, Bai F, Painter JS, Rollison DE, Salih HR, Krusch M, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007;109:4816–24.

    CAS  Article  Google Scholar 

  65. Garcia-Manero G, Daver NG, Montalban-Bravo G, Jabbour EJ, DiNardo CD, Kornblau SM, et al. A phase II study evaluating the combination of nivolumab or ipilimumab with azacitidine in patients with previously treated or untreated myelodysplastic syndromes. American Society of Hematology; Blood 2016;128:344.

  66. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143–53.

    CAS  Article  Google Scholar 

  67. Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget. 2013;4:2067–79.

    Article  Google Scholar 

  68. Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol. 2015;6:29.

    PubMed  PubMed Central  Google Scholar 

  69. Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5:587–98.

    PubMed  PubMed Central  Google Scholar 

  70. Srivastava P, Paluch BE, Matsuzaki J, James SR, Collamat-Lai G, Blagitko-Dorfs N, et al. Induction of cancer testis antigen expression in circulating acute myeloid leukemia blasts following hypomethylating agent monotherapy. Oncotarget. 2016;7:12840–56.

    Article  Google Scholar 

  71. Coral S, Sigalotti L, Altomonte M, Engelsberg A, Colizzi F, Cattarossi I, et al. 5-aza-2’-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications. Clin Cancer Res. 2002;8:2690–5.

    CAS  PubMed  Google Scholar 

  72. Coral S, Sigalotti L, Gasparollo A, Cattarossi I, Visintin A, Cattelan A, et al. Prolonged upregulation of the expression of HLA class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2’-deoxycytidine (5-AZA-CdR). J Immunother. 1999;22:16–24.

    CAS  Article  Google Scholar 

  73. Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G, et al. Induction of a CD8 + T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116:1908–18.

    CAS  Article  Google Scholar 

  74. Costantini B, Kordasti SY, Kulasekararaj AG, Jiang J, Seidl T, Abellan PP, et al. The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica. 2013;98:1196–205.

    CAS  Article  Google Scholar 

  75. Catakovic K, Klieser E, Neureiter D, Geisberger R. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 2017;15:1.

    Article  Google Scholar 

  76. Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS, West EE, et al. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells. Immunity. 2011;35:400–12.

    CAS  Article  Google Scholar 

  77. Orskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M, et al. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget. 2015;6:9612–26.

    Article  Google Scholar 

  78. Perez-Gracia JL, Labiano S, Rodriguez-Ruiz ME, Sanmamed MF, Melero I. Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Curr Opin Immunol. 2014;27:89–97.

    CAS  Article  Google Scholar 

  79. Karpf AR, Peterson PW, Rawlins JT, Dalley BK, Yang Q, Albertsen H, et al. Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc Natl Acad Sci USA. 1999;96:14007–12.

    CAS  Article  Google Scholar 

  80. Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162:961–73.

    CAS  Article  Google Scholar 

  81. Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2017;169:361.

    CAS  Article  Google Scholar 

  82. Daver N, Basu S, Garcia-Manero G, Cortes JE, Ravandi F, Jabbour EJ, et al. Phase IB/II study of nivolumab in combination with azacytidine in patients with relapsed acute myeloid leukemia. American Society of Hematology (616); Blood. 2016;128:763.

Download references

Author contributions

ND, PB performed the research for the review, were involved in writing the paper and share co-authorship. GGM, SSY, JA, PS, HK involved in providing intellectual content, writing and reviewing the manuscript.

Funding

This manuscript was supported in part by the MD Anderson Cancer Center Leukemia Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif Souki Cancer Research Fund, and generous philanthropic contributions to the MD Anderson Moon Shots Program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Naval Daver.

Ethics declarations

Conflict of interest

ND has received research funding from BMS, Pfizer, Merck, and served as a consultant for BMS, Pfizer, and Celgene. HK has received research funding from BMS, Pfizer, and served as a consultant for Pfizer. PS and JA have served as consultants for BMS, EMD Serrono, and AstraZeneca. The remaining authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Daver, N., Boddu, P., Garcia-Manero, G. et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia 32, 1094–1105 (2018). https://doi.org/10.1038/s41375-018-0070-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0070-8

Further reading

Search

Quick links