Skip to main content

Advertisement

Springer Nature Link
Log in

The progress and current status of immunotherapy in acute myeloid leukemia

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Recently, there has been remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML). The improved outcomes of AML can largely be attributed to advances in supportive care and hematopoietic cell transplantation as opposed to conventional chemotherapy. However, as the 5-year survival rate remains low due to a high incidence of relapse, novel and effective treatments are urgently needed. Increasing attention is focusing on identifying suitable immunotherapeutic strategies for AML. Here, we describe the immunological features, mechanisms of immune escape, and recent progress in immunotherapy for AML. Problems encountered in the clinic will also be discussed. Although current outcomes may be limited, ongoing preclinical or clinical efforts are aimed at improving immunotherapy modalities and designing novel therapies, such as vaccines, monoclonal antibody therapy, chimeric antibody receptor-engineered T cells (CAR-T), TCR-engineered T cells (TCR-T), and checkpoint inhibitors, which may provide promising and effective therapies with higher specificity and efficacy for AML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wiseman DH, Greystoke BF, Somervaille TC (2014) The variety of leukemic stem cells in myeloid malignancy. Oncogene 33(24):3091–3098. https://doi.org/10.1038/onc.2013.269

    Article  CAS  PubMed  Google Scholar 

  2. Pleyer L, Stauder R, Burgstaller S, Schreder M, Tinchon C, Pfeilstocker M, Steinkirchner S, Melchardt T, Mitrovic M, Girschikofsky M, Lang A, Krippl P, Sliwa T, Egle A, Linkesch W, Voskova D, Angermann H, Greil R (2013) Azacitidine in patients with WHO-defined AML—results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group. J Hematol Oncol 6:32. https://doi.org/10.1186/1756-8722-6-32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yates JW, Wallace HJ Jr, Ellison RR, Holland JF (1973) Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 57(4):485–488

    CAS  PubMed  Google Scholar 

  4. Barrett AJ (2008) Understanding and harnessing the graft-versus-leukaemia effect. Br J Haematol 142(6):877–888. https://doi.org/10.1111/j.1365-2141.2008.07260.x

    Article  CAS  PubMed  Google Scholar 

  5. Whiteway A, Corbett T, Anderson R, Macdonald I, Prentice HG (2003) Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission. Br J Haematol 120(3):442–451

    Article  CAS  PubMed  Google Scholar 

  6. Cheng K, Wong SC, Linn YC, Ho LP, Chng WJ, Schwarz H (2014) CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells. Br J Haematol 165(1):134–144. https://doi.org/10.1111/bjh.12732

    Article  CAS  PubMed  Google Scholar 

  7. Shen M, Linn YC, Ren EC (2016) KIR-HLA profiling shows presence of higher frequencies of strong inhibitory KIR-ligands among prognostically poor risk AML patients. Immunogenetics 68(2):133–144. https://doi.org/10.1007/s00251-015-0888-4

    Article  CAS  PubMed  Google Scholar 

  8. Tang M, Acheampong DO, Wang Y, Xie W, Wang M, Zhang J (2016) Tumoral NKG2D alters cell cycle of acute myeloid leukemic cells and reduces NK cell-mediated immune surveillance. Immunol Res 64(3):754–764. https://doi.org/10.1007/s12026-015-8769-3

    Article  CAS  PubMed  Google Scholar 

  9. Benitez AC, Dai Z, Mann HH, Reeves RS, Margineantu DH, Gooley TA, Groh V, Spies T (2011) Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells. Proc Natl Acad Sci U S A 108(10):4081–4086. https://doi.org/10.1073/pnas.1018603108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lion E, Willemen Y, Berneman ZN, Van Tendeloo VF, Smits EL (2012) Natural killer cell immune escape in acute myeloid leukemia. Leukemia 26(9):2019–2026. https://doi.org/10.1038/leu.2012.87

    Article  CAS  PubMed  Google Scholar 

  11. Baessler T, Krusch M, Schmiedel BJ, Kloss M, Baltz KM, Wacker A, Schmetzer HM, Salih HR (2009) Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans. Cancer Res 69(3):1037–1045. https://doi.org/10.1158/0008-5472.can-08-2650

    Article  CAS  PubMed  Google Scholar 

  12. Steinbacher J, Schmiedel BJ, Werner A, Nuebling T, Buechele C, Grosse-Hovest L, Kanz L, Salih HR (2012) Bimodal induction of NK cell reactivity against acute myeloid (AML) and chronic lymphoid leukemia (CLL) by Fc-engineered GITR-Fc fusion proteins [abstract]. Blood 120(21):2143

  13. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, Fang Z, Nguyen M, Pierce S, Wei Y, Parmar S, Cortes J, Kantarjian H, Garcia-Manero G (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28(6):1280–1288. https://doi.org/10.1038/leu.2013.355

    Article  CAS  PubMed  Google Scholar 

  14. Salih HR, Schmetzer HM, Burke C, Starling GC, Dunn R, Pelka-Fleischer R, Nuessler V, Kiener PA (2001) Soluble CD137 (4-1BB) ligand is released following leukocyte activation and is found in sera of patients with hematological malignancies. J Immunol 167(7):4059–4066

    Article  CAS  PubMed  Google Scholar 

  15. Scholl N, Loibl J, Kremser A, Liepert A, Grabrucker C, Salih HR, Kolb HJ, Schmetzer HM (2009) The role of soluble and cell-surface expressed 4-1BB ligand in patients with malignant hemopoietic disorders. Leuk Lymphoma 50(3):427–436. https://doi.org/10.1080/10428190802709453

    Article  CAS  PubMed  Google Scholar 

  16. Le Dieu R, Taussig DC, Ramsay AG, Mitter R, Miraki-Moud F, Fatah R, Lee AM, Lister TA, Gribben JG (2009) 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 114(18):3909–3916. https://doi.org/10.1182/blood-2009-02-206946

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Khaznadar Z, Henry G, Setterblad N, Agaugue S, Raffoux E, Boissel N, Dombret H, Toubert A, Dulphy N (2014) Acute myeloid leukemia impairs natural killer cells through the formation of a deficient cytotoxic immunological synapse. Eur J Immunol 44(10):3068–3080. https://doi.org/10.1002/eji.201444500

    Article  CAS  PubMed  Google Scholar 

  18. Buggins AG, Milojkovic D, Arno MJ, Lea NC, Mufti GJ, Thomas NS, Hirst WJ (2001) Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappaB, c-Myc, and pRb pathways. J Immunol 167(10):6021–6030

    Article  CAS  PubMed  Google Scholar 

  19. Li Y, Yin Q, Yang L, Chen S, Geng S, Wu X, Zhong L, Schmidt CA, Przybylski GK (2009) Reduced levels of recent thymic emigrants in acute myeloid leukemia patients. Cancer Immunol Immunother: CII 58(7):1047–1055. https://doi.org/10.1007/s00262-008-0621-3

    Article  CAS  PubMed  Google Scholar 

  20. Driss V, Quesnel B, Brinster C (2015) Monocyte chemoattractant protein 1 (MCP-1/CCL2) contributes to thymus atrophy in acute myeloid leukemia. Eur J Immunol 45(2):396–406. https://doi.org/10.1002/eji.201444736

    Article  CAS  PubMed  Google Scholar 

  21. Cogle CR, Bosse RC, Brewer T, Migdady Y, Shirzad R, Kampen KR, Saki N (2016) Acute myeloid leukemia in the vascular niche. Cancer Lett 380(2):552–560. https://doi.org/10.1016/j.canlet.2015.05.007

    Article  CAS  PubMed  Google Scholar 

  22. Ishii K, Barrett AJ (2016) Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic). Ther Adv Hematol 7(1):17–39. https://doi.org/10.1177/2040620715616544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, Vellenga E, De Greef GE, Jacky E, Van der Lelie J, Boogaerts MA, Lowenberg B (2005) Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 23(9):1969–1978. https://doi.org/10.1200/jco.2005.06.027

    Article  PubMed  Google Scholar 

  24. Powles RL, Balchin LA, Fairley GH, Alexander P (1971) Recognition of leukaemia cells as foreign before and after autoimmunization. Br Med J 1(5747):486–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Van Tendeloo VF, Van Broeckhoven C, Berneman ZN (2001) Gene-based cancer vaccines: an ex vivo approach. Leukemia 15(4):545–558

    Article  PubMed  CAS  Google Scholar 

  26. Zhang WG, Liu SH, Cao XM, Cheng YX, Ma XR, Yang Y, Wang YL (2005) A phase-I clinical trial of active immunotherapy for acute leukemia using inactivated autologous leukemia cells mixed with IL-2, GM-CSF, and IL-6. Leuk Res 29(1):3–9. https://doi.org/10.1016/j.leukres.2004.04.015

    Article  CAS  PubMed  Google Scholar 

  27. Smits EL, Ponsaerts P, Van de Velde AL, Van Driessche A, Cools N, Lenjou M, Nijs G, Van Bockstaele DR, Berneman ZN, Van Tendeloo VF (2007) Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells. Leukemia 21(8):1691–1699. https://doi.org/10.1038/sj.leu.2404763

    Article  CAS  PubMed  Google Scholar 

  28. Greiner J, Dohner H, Schmitt M (2006) Cancer vaccines for patients with acute myeloid leukemia—definition of leukemia-associated antigens and current clinical protocols targeting these antigens. Haematologica 91(12):1653–1661

    CAS  PubMed  Google Scholar 

  29. Kwon M, Martinez-Laperche C, Infante M, Carretero F, Balsalobre P, Serrano D, Gayoso J, Perez-Corral A, Anguita J, Diez-Martin JL, Buno I (2012) Evaluation of minimal residual disease by real-time quantitative PCR of Wilms’ tumor 1 expression in patients with acute myelogenous leukemia after allogeneic stem cell transplantation: correlation with flow cytometry and chimerism. Biol Blood Marrow Transplant 18(8):1235–1242. https://doi.org/10.1016/j.bbmt.2012.01.012

    Article  CAS  PubMed  Google Scholar 

  30. Tsuboi A, Oka Y, Kyo T, Katayama Y, Elisseeva OA, Kawakami M, Nishida S, Morimoto S, Murao A, Nakajima H, Hosen N, Oji Y, Sugiyama H (2012) Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease. Leukemia 26(6):1410–1413. https://doi.org/10.1038/leu.2011.343

    Article  CAS  PubMed  Google Scholar 

  31. Liu H, Zha Y, Malnassy G, Fulton N, Green M, Park J-H, Nakamura Y, Larson RA, Salazar AM, Odenike O, Gajewski T, Stock W (2016) WT1 peptide vaccine is able to induce WT1-specifc immune response with TCR clonal enrichment to control minimal residual disease in patients with myeloid leukemia [abstract]. Blood 128(22):3984

  32. Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, Fukushima P, Barrett AJ (1996) Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 88(7):2450–2457

    CAS  PubMed  Google Scholar 

  33. Ma Q, Wang C, Jones D, Quintanilla KE, Li D, Wang Y, Wieder ED, Clise-Dwyer K, Alatrash G, Mj Y, Munsell MF, Lu S, Qazilbash MH, Molldrem JJ (2010) Adoptive transfer of PR1 cytotoxic T lymphocytes associated with reduced leukemia burden in a mouse acute myeloid leukemia xenograft model. Cytotherapy 12(8):1056–1062. https://doi.org/10.3109/14653249.2010.506506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sergeeva A, He H, Ruisaard K, St John L, Alatrash G, Clise-Dwyer K, Li D, Patenia R, Hong R, Sukhumalchandra P, You MJ, Gagea M, Ma Q, Molldrem JJ (2016) Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo. Leukemia 30(7):1475–1484. https://doi.org/10.1038/leu.2016.57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ma Q, Garber HR, Lu S, He H, Tallis E, Ding X, Sergeeva A, Wood MS, Dotti G, Salvado B, Ruisaard K, Clise-Dwyer K, John LS, Rezvani K, Alatrash G, Shpall EJ, Molldrem JJ (2016) A novel TCR-like CAR with specificity for PR1/HLA-A2 effectively targets myeloid leukemia in vitro when expressed in human adult peripheral blood and cord blood T cells. Cytotherapy 18(8):985–994. https://doi.org/10.1016/j.jcyt.2016.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Qazilbash MH, Wieder E, Thall PF, Wang X, Rios R, Lu S, Kanodia S, Ruisaard KE, Giralt SA, Estey EH, Cortes J, Komanduri KV, Clise-Dwyer K, Alatrash G, Ma Q, Champlin RE, Molldrem JJ (2017) PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies. Leukemia 31(3):697–704. https://doi.org/10.1038/leu.2016.254

    Article  CAS  PubMed  Google Scholar 

  37. Ding K, Wang XM, Fu R, Ruan EB, Liu H, Shao ZH (2012) PRAME gene expression in acute leukemia and its clinical significance. Cancer Biol Med 9(1):73–76. https://doi.org/10.3969/j.issn.2095-3941.2012.01.013

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Quintarelli C, Dotti G, Hasan ST, De Angelis B, Hoyos V, Errichiello S, Mims M, Luciano L, Shafer J, Leen AM, Heslop HE, Rooney CM, Pane F, Brenner MK, Savoldo B (2011) High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells. Blood 117(12):3353–3362. https://doi.org/10.1182/blood-2010-08-300376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sherman L, Sleeman J, Herrlich P, Ponta H (1994) Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. Curr Opin Cell Biol 6(5):726–733

    Article  CAS  PubMed  Google Scholar 

  40. Greiner J, Ringhoffer M, Taniguchi M, Li L, Schmitt A, Shiku H, Dohner H, Schmitt M (2004) mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int J Cancer 108(5):704–711. https://doi.org/10.1002/ijc.11623

    Article  CAS  PubMed  Google Scholar 

  41. Schmitt M, Schmitt A, Rojewski MT, Chen J, Giannopoulos K, Fei F, Yu Y, Gotz M, Heyduk M, Ritter G, Speiser DE, Gnjatic S, Guillaume P, Ringhoffer M, Schlenk RF, Liebisch P, Bunjes D, Shiku H, Dohner H, Greiner J (2008) RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood 111(3):1357–1365. https://doi.org/10.1182/blood-2007-07-099366

    Article  CAS  PubMed  Google Scholar 

  42. Spranger S, Jeremias I, Wilde S, Leisegang M, Starck L, Mosetter B, Uckert W, Heemskerk MH, Schendel DJ, Frankenberger B (2012) TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo. Blood 119(15):3440–3449. https://doi.org/10.1182/blood-2011-06-357939

    Article  CAS  PubMed  Google Scholar 

  43. Rezvani K, Yong AS, Mielke S, Savani BN, Musse L, Superata J, Jafarpour B, Boss C, Barrett AJ (2008) Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 111(1):236–242. https://doi.org/10.1182/blood-2007-08-108241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cools N, Ponsaerts P, Van Tendeloo VF, Berneman ZN (2007) Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector T cells. J Leukoc Biol 82(6):1365–1374. https://doi.org/10.1189/jlb.0307166

    Article  CAS  PubMed  Google Scholar 

  45. Meidenbauer N, Andreesen R, Mackensen A (2001) Dendritic cells for specific cancer immunotherapy. Biol Chem 382(4):507–520. https://doi.org/10.1515/bc.2001.065

    Article  CAS  PubMed  Google Scholar 

  46. Subklewe M, Geiger C, Lichtenegger FS, Javorovic M, Kvalheim G, Schendel DJ, Bigalke I (2014) New generation dendritic cell vaccine for immunotherapy of acute myeloid leukemia. Cancer Immunol Immunother: CII 63(10):1093–1103. https://doi.org/10.1007/s00262-014-1600-5

    Article  CAS  PubMed  Google Scholar 

  47. Pyzer AR, Avigan DE, Rosenblatt J (2014) Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies. Hum Vaccin Immunother 10(11):3125–3131. https://doi.org/10.4161/21645515.2014.982993

    Article  PubMed  Google Scholar 

  48. Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries IJ, Price DA, Oji Y, Oka Y, Sugiyama H, Berneman ZN (2010) Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A 107(31):13824–13829. https://doi.org/10.1073/pnas.1008051107

    Article  PubMed  PubMed Central  Google Scholar 

  49. Berneman ZN, Velde ALVd, Willemen Y, Anguille S, Saevels K, Germonpré P, Huizing MT, Peeters M, Snoeckx A, Parizel P, Tendeloo VFV, Lion E, Nijs G, Stein B, Vermeulen K, Maes M-B, Malfait R, Vrelust I, Verlinden A, Gadisseur AP, Schroyens WA, Lammens M, Smits EL (2014) Vaccination with WT1 mRNA-electroporated dendritic cells: report of clinical outcome in 66 cancer patients [abstract]. Blood 124(21):310

  50. Padua RA, Larghero J, Robin M, le Pogam C, Schlageter MH, Muszlak S, Fric J, West R, Rousselot P, Phan TH, Mudde L, Teisserenc H, Carpentier AF, Kogan S, Degos L, Pla M, Bishop JM, Stevenson F, Charron D, Chomienne C (2003) PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia. Nat Med 9(11):1413–1417. https://doi.org/10.1038/nm949

    Article  CAS  PubMed  Google Scholar 

  51. Tagawa ST, Lee P, Snively J, Boswell W, Ounpraseuth S, Lee S, Hickingbottom B, Smith J, Johnson D, Weber JS (2003) Phase I study of intranodal delivery of a plasmid DNA vaccine for patients with Stage IV melanoma. Cancer 98(1):144–154. https://doi.org/10.1002/cncr.11462

    Article  CAS  PubMed  Google Scholar 

  52. Timmerman JM, Singh G, Hermanson G, Hobart P, Czerwinski DK, Taidi B, Rajapaksa R, Caspar CB, Van Beckhoven A, Levy R (2002) Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res 62(20):5845–5852

    CAS  PubMed  Google Scholar 

  53. Lin C, Li Y (2013) The role of peptide and DNA vaccines in myeloid leukemia immunotherapy. Cancer Cell Int 13(1):13. https://doi.org/10.1186/1475-2867-13-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kohler G, Milstein C (2005) Continuous cultures of fused cells secreting antibody of predefined specificity. 1975. J Immunol 174(5):2453–2455

    CAS  PubMed  Google Scholar 

  55. Cowan AJ, Laszlo GS, Estey EH, Walter RB (2013) Antibody-based therapy of acute myeloid leukemia with gemtuzumab ozogamicin. Front Biosci (Landmark Ed) 18:1311–1334

    Article  CAS  Google Scholar 

  56. Feldman E, Kalaycio M, Weiner G, Frankel S, Schulman P, Schwartzberg L, Jurcic J, Velez-Garcia E, Seiter K, Scheinberg D, Levitt D, Wedel N (2003) Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195. Leukemia 17(2):314–318. https://doi.org/10.1038/sj.leu.2402803

    Article  CAS  PubMed  Google Scholar 

  57. Caron PC, Dumont L, Scheinberg DA (1998) Supersaturating infusional humanized anti-CD33 monoclonal antibody HuM195 in myelogenous leukemia. Clin Cancer Res 4(6):1421–1428

    CAS  PubMed  Google Scholar 

  58. Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR, Panageas KS, Heaney ML, Chanel S, Morgenstern A, Sgouros G, Larson SM, Scheinberg DA, Jurcic JG (2010) Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res 16(21):5303–5311. https://doi.org/10.1158/1078-0432.ccr-10-0382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Damle NK, Frost P (2003) Antibody-targeted chemotherapy with immunoconjugates of calicheamicin. Curr Opin Pharmacol 3(4):386–390

    Article  CAS  PubMed  Google Scholar 

  60. Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 29(4):369–377. https://doi.org/10.1200/jco.2010.31.4310

    Article  CAS  PubMed  Google Scholar 

  61. Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR (2013) A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121(24):4854–4860. https://doi.org/10.1182/blood-2013-01-466706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ravandi F, Estey EH, Appelbaum FR, Lo-Coco F, Schiffer CA, Larson RA, Burnett AK, Kantarjian HM (2012) Gemtuzumab ozogamicin: time to resurrect? J Clin Oncol 30(32):3921–3923. https://doi.org/10.1200/jco.2012.43.0132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F (2016) Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol 34(9):972–979. https://doi.org/10.1200/jco.2015.64.0060

    Article  PubMed  CAS  Google Scholar 

  64. Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, Lyon RP, Zeng W, Harrington KH, Klussman K, Westendorf L, Meyer D, Bernstein ID, Senter PD, Benjamin DR, Drachman JG, McEarchern JA (2013) SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122(8):1455–1463. https://doi.org/10.1182/blood-2013-03-491506

    Article  PubMed  CAS  Google Scholar 

  65. Stein EM (2014) Interim analysis of a phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia (AML). Blood Abstract 124:623

    Google Scholar 

  66. Krystal WM, Walker R, Fishkin N, Audette C, Kovtun Y, Romanelli A (2015) IMGN779, a CD33-targeted antibody-drug conjugate (ADC) with a novel DNA-alkylating effector molecule, induces DNA damage, cell cycle arrest, and apoptosis in AML cells [abstract]. Blood 126(23):1366

  67. Portwood S, Puchalski RA, Walker RM, Wang ES (2016) Combining IMGN779, a novel anti-CD33 antibody-drug conjugate (ADC), with the PARP inhibitor, olaparib, results in enhanced anti-tumor activity in preclinical acute myeloid leukemia (AML) models [abstract]. Blood 128(22):1645

  68. Borthakur G, Rosenblum MG, Talpaz M, Daver N, Ravandi F, Faderl S, Freireich EJ, Kadia T, Garcia-Manero G, Kantarjian H, Cortes JE (2013) Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies. Haematologica 98(2):217–221. https://doi.org/10.3324/haematol.2012.071092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Munoz L, Nomdedeu JF, Lopez O, Carnicer MJ, Bellido M, Aventin A, Brunet S, Sierra J (2001) Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica 86(12):1261–1269

    CAS  PubMed  Google Scholar 

  70. Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, Latagliata R, Mariani G, Rossini A, Battistini A, Lo-Coco F, Peschle C (2002) Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood 100(8):2980–2988. https://doi.org/10.1182/blood-2002-03-0852

    Article  CAS  PubMed  Google Scholar 

  71. He SZ, Busfield S, Ritchie DS, Hertzberg MS, Durrant S, Lewis ID, Marlton P, McLachlan AJ, Kerridge I, Bradstock KF, Kennedy G, Boyd AW, Yeadon TM, Lopez AF, Ramshaw HS, Iland H, Bamford S, Barnden M, DeWitte M, Basser R, Roberts AW (2015) A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk Lymphoma 56(5):1406–1415. https://doi.org/10.3109/10428194.2014.956316

    Article  CAS  PubMed  Google Scholar 

  72. Smith BD, Roboz GJ, Walter RB, Altman JK, Ferguson A, Curcio TJ, Orlowski KF, Garrett L, Busfield SJ, Barnden M, Sedgmen B, Ghosh S, Hosback S, Davis R, Dyson A, Dasen S, DeWitte M, Bensen-Kennedy DM, Roberts AW (2014) First-in man, phase 1 study of CSL362 (anti-IL3Rα/anti-CD123 monoclonal antibody) in patients with CD123+ acute myeloid leukemia (AML) in CR at high risk for early relapse [abstract]. Blood 124(21):120

  73. Sweet KL, Pemmaraju N, Lane AA, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Rowinsky EK, Szarek M, Brooks CL, Disalvatore S, Liu D, Duvic M, Schwartz JD, Konopleva M (2015) Lead-in stage results of a pivotal trial of SL-401, an interleukin-3 receptor (IL-3R) targeting biologic, in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) or acute myeloid leukemia (AML) [abstract]. Blood 126(23):3795

  74. Schwartz MA, Lovett DR, Redner A, Finn RD, Graham MC, Divgi CR, Dantis L, Gee TS, Andreeff M, Old LJ et al (1993) Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias. J Clin Oncol 11(2):294–303

    Article  CAS  PubMed  Google Scholar 

  75. Jurcic JG (2012) What happened to anti-CD33 therapy for acute myeloid leukemia? Curr Hematol Malig Rep 7(1):65–73. https://doi.org/10.1007/s11899-011-0103-0

    Article  PubMed  Google Scholar 

  76. Pagel JM, Gooley TA, Rajendran J, Fisher DR, Wilson WA, Sandmaier BM, Matthews DC, Deeg HJ, Gopal AK, Martin PJ, Storb RF, Press OW, Appelbaum FR (2009) Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 114(27):5444–5453. https://doi.org/10.1182/blood-2009-03-213298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pagel JM, Appelbaum FR, Eary JF, Rajendran J, Fisher DR, Gooley T, Ruffner K, Nemecek E, Sickle E, Durack L, Carreras J, Horowitz MM, Press OW, Gopal AK, Martin PJ, Bernstein ID, Matthews DC (2006) 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood 107(5):2184–2191. https://doi.org/10.1182/blood-2005-06-2317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Burke JM, Caron PC, Papadopoulos EB, Divgi CR, Sgouros G, Panageas KS, Finn RD, Larson SM, O'Reilly RJ, Scheinberg DA, Jurcic JG (2003) Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant 32(6):549–556. https://doi.org/10.1038/sj.bmt.1704201

    Article  CAS  PubMed  Google Scholar 

  79. Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, Ballangrud AM, Hamacher KA, Ma D, Humm JL, Brechbiel MW, Molinet R, Scheinberg DA (2002) Targeted alpha particle immunotherapy for myeloid leukemia. Blood 100(4):1233–1239

    CAS  PubMed  Google Scholar 

  80. Jurcic JG, Levy MY, Park JH, Ravandi F, Perl AE, Pagel JM, Smith BD, Estey EH, Kantarjian H, Cicic D, Scheinberg DA (2016) Phase I trial of targeted alpha-particle therapy with actinium-225 (225Ac)-lintuzumab and low-dose cytarabine (LDAC) in patients age 60 or older with untreated acute myeloid leukemia (AML) [abstract]. Blood 128(22):4050

  81. Orozco JJ, Back T, Kenoyer A, Balkin ER, Hamlin DK, Wilbur DS, Fisher DR, Frayo SL, Hylarides MD, Green DJ, Gopal AK, Press OW, Pagel JM (2013) Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model. Blood 121(18):3759–3767. https://doi.org/10.1182/blood-2012-11-467035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Kohne-Volland R, Bruggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmuller G, Hoelzer D, Zugmaier G, Bargou RC (2011) Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 29(18):2493–2498. https://doi.org/10.1200/jco.2010.32.7270

    Article  CAS  PubMed  Google Scholar 

  83. Krupka C, Kufer P, Kischel R, Zugmaier G, Bogeholz J, Kohnke T, Lichtenegger FS, Schneider S, Metzeler KH, Fiegl M, Spiekermann K, Baeuerle PA, Hiddemann W, Riethmuller G, Subklewe M (2014) CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood 123(3):356–365. https://doi.org/10.1182/blood-2013-08-523548

    Article  CAS  PubMed  Google Scholar 

  84. Laszlo GS, Gudgeon CJ, Harrington KH, Dell'Aringa J, Newhall KJ, Means GD, Sinclair AM, Kischel R, Frankel SR, Walter RB (2014) Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Blood 123(4):554–561. https://doi.org/10.1182/blood-2013-09-527044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Johnson S, Burke S, Huang L, Gorlatov S, Li H, Wang W, Zhang W, Tuaillon N, Rainey J, Barat B, Yang Y, Jin L, Ciccarone V, Moore PA, Koenig S, Bonvini E (2010) Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol 399(3):436–449. https://doi.org/10.1016/j.jmb.2010.04.001

    Article  CAS  PubMed  Google Scholar 

  86. Al-Hussaini M, Rettig MP, Ritchey JK, Karpova D, Uy GL, Eissenberg LG, Gao F, Eades WC, Bonvini E, Chichili GR, Moore PA, Johnson S, Collins L, DiPersio JF (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127(1):122–131. https://doi.org/10.1182/blood-2014-05-575704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rosenberg SA, Lotze MT, Yang JC, Topalian SL, Chang AE, Schwartzentruber DJ, Aebersold P, Leitman S, Linehan WM, Seipp CA et al (1993) Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 85(8):622–632

    Article  CAS  PubMed  Google Scholar 

  88. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT et al (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316(15):889–897. https://doi.org/10.1056/nejm198704093161501

    Article  CAS  PubMed  Google Scholar 

  89. Ettinghausen SE, Lipford EH 3rd, Mule JJ, Rosenberg SA (1985) Recombinant interleukin 2 stimulates in vivo proliferation of adoptively transferred lymphokine-activated killer (LAK) cells. J Immunol 135(5):3623–3635

    CAS  PubMed  Google Scholar 

  90. Thatcher N, Dazzi H, Johnson RJ, Russell S, Ghosh AK, Moore M, Chadwick G, Craig RD (1989) Recombinant interleukin-2 (rIL-2) given intrasplenically and intravenously for advanced malignant melanoma. A phase I and II study. Br J Cancer 60(5):770–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lu PH, Negrin RS (1994) A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol 153(4):1687–1696

    CAS  PubMed  Google Scholar 

  92. Borrello I, Noonan KA (2016) Marrow-infiltrating lymphocytes—role in biology and cancer therapy. Front Immunol 7:112. https://doi.org/10.3389/fimmu.2016.00112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Noonan KA, Huff CA, Davis J, Lemas MV, Fiorino S, Bitzan J, Ferguson A, Emerling A, Luznik L, Matsui W, Powell J, Fuchs E, Rosner GL, Epstein C, Rudraraju L, Ambinder RF, Jones RJ, Pardoll D, Borrello I (2015) Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med 7(288):288ra278. https://doi.org/10.1126/scitranslmed.aaa7014

    Article  CAS  Google Scholar 

  94. Kapp M, Stevanovic S, Fick K, Tan SM, Loeffler J, Opitz A, Tonn T, Stuhler G, Einsele H, Grigoleit GU (2009) CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT. Bone Marrow Transplant 43(5):399–410. https://doi.org/10.1038/bmt.2008.426

    Article  CAS  PubMed  Google Scholar 

  95. Amir AL, van der Steen DM, van Loenen MM, Hagedoorn RS, de Boer R, Kester MD, de Ru AH, Lugthart GJ, van Kooten C, Hiemstra PS, Jedema I, Griffioen M, van Veelen PA, Falkenburg JH, Heemskerk MH (2011) PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer. Clin Cancer Res 17(17):5615–5625. https://doi.org/10.1158/1078-0432.ccr-11-1066

    Article  CAS  PubMed  Google Scholar 

  96. Mohamed YS, Bashawri LA, Vatte C, Abu-Rish EY, Cyrus C, Khalaf WS, Browning MJ (2016) The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation. Mol Immunol 77:79–88. https://doi.org/10.1016/j.molimm.2016.07.012

    Article  CAS  PubMed  Google Scholar 

  97. Leung W (2014) Infusions of allogeneic natural killer cells as cancer therapy. Clin Cancer Res 20(13):3390–3400. https://doi.org/10.1158/1078-0432.ccr-13-1766

    Article  CAS  PubMed  Google Scholar 

  98. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science (New York, NY) 295(5562):2097–2100. https://doi.org/10.1126/science.1068440

    Article  CAS  Google Scholar 

  99. Choi I, Yoon SR, Park SY, Kim H, Jung SJ, Jang YJ, Kang M, Yeom YI, Lee JL, Kim DY, Lee YS, Kang YA, Jeon M, Seol M, Lee JH, Lee JH, Kim HJ, Yun SC, Lee KH (2014) Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Biol Blood Marrow Transplant 20(5):696–704. https://doi.org/10.1016/j.bbmt.2014.01.031

    Article  CAS  PubMed  Google Scholar 

  100. Dulphy N, Chretien AS, Khaznadar Z, Fauriat C, Nanbakhsh A, Caignard A, Chouaib S, Olive D, Toubert A (2016) Underground adaptation to a hostile environment: acute myeloid leukemia vs. natural killer cells. Front Immunol 7:94. https://doi.org/10.3389/fimmu.2016.00094

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Sandoval-Borrego D, Moreno-Lafont MC, Vazquez-Sanchez EA, Gutierrez-Hoya A, Lopez-Santiago R, Montiel-Cervantes LA, Ramirez-Saldana M, Vela-Ojeda J (2016) Overexpression of CD158 and NKG2A inhibitory receptors and underexpression of NKG2D and NKp46 activating receptors on NK cells in acute myeloid leukemia. Arch Med Res 47(1):55–64. https://doi.org/10.1016/j.arcmed.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  102. Koehl U, Sorensen J, Esser R, Zimmermann S, Gruttner HP, Tonn T, Seidl C, Seifried E, Klingebiel T, Schwabe D (2004) IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation. Blood Cells Mol Dis 33(3):261–266. https://doi.org/10.1016/j.bcmd.2004.08.013

    Article  CAS  PubMed  Google Scholar 

  103. Stern M, Passweg JR, Meyer-Monard S, Esser R, Tonn T, Soerensen J, Paulussen M, Gratwohl A, Klingebiel T, Bader P, Tichelli A, Schwabe D, Koehl U (2013) Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers. Bone Marrow Transplant 48(3):433–438. https://doi.org/10.1038/bmt.2012.162

    Article  CAS  PubMed  Google Scholar 

  104. Chang YH, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D (2013) A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res 73(6):1777–1786. https://doi.org/10.1158/0008-5472.can-12-3558

    Article  CAS  PubMed  Google Scholar 

  105. Kamiya T, Chang YH, Campana D (2016) Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma. Cancer Immunol Res 4(7):574–581. https://doi.org/10.1158/2326-6066.cir-15-0229

    Article  CAS  PubMed  Google Scholar 

  106. Hermanson DL, Kaufman DS (2015) Utilizing chimeric antigen receptors to direct natural killer cell activity. Front Immunol 6:195. https://doi.org/10.3389/fimmu.2015.00195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Linn YC, Lau SK, Liu BH, Ng LH, Yong HX, Hui KM (2009) Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology 126(3):423–435. https://doi.org/10.1111/j.1365-2567.2008.02910.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Introna M, Golay J, Rambaldi A (2013) Cytokine induced killer (CIK) cells for the treatment of haematological neoplasms. Immunol Lett 155(1-2):27–30. https://doi.org/10.1016/j.imlet.2013.09.017

    Article  CAS  PubMed  Google Scholar 

  109. Sangiolo D (2011) Cytokine induced killer cells as promising immunotherapy for solid tumors. J Cancer 2:363–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rettinger E, Meyer V, Kreyenberg H, Volk A, Kuci S, Willasch A, Koscielniak E, Fulda S, Wels WS, Boenig H, Klingebiel T, Bader P (2012) Cytotoxic capacity of IL-15-stimulated cytokine-induced killer cells against human acute myeloid leukemia and rhabdomyosarcoma in humanized preclinical mouse models. Front Oncol 2:32. https://doi.org/10.3389/fonc.2012.00032

    Article  PubMed  PubMed Central  Google Scholar 

  111. Linn YC, Niam M, Chu S, Choong A, Yong HX, Heng KK, Hwang W, Loh Y, Goh YT, Suck G, Chan M, Koh M (2012) The anti-tumour activity of allogeneic cytokine-induced killer cells in patients who relapse after allogeneic transplant for haematological malignancies. Bone Marrow Transplant 47(7):957–966. https://doi.org/10.1038/bmt.2011.202

    Article  CAS  PubMed  Google Scholar 

  112. Zhong ZD, Luo Y, Zou P, Zheng JE, Yao JX, Huang SA, Zhou DF, You Y (2012) Infusions of recipient-derived cytokine-induced killer cells of donor origin eradicated residual disease in a relapsed leukemia patient after allo-hematopoietic stem cell transplantation. Chin Med J 125(9):1669–1671

    PubMed  Google Scholar 

  113. Marten A, Renoth S, von Lilienfeld-Toal M, Buttgereit P, Schakowski F, Glasmacher A, Sauerbruch T, Schmidt-Wolf IG (2001) Enhanced lytic activity of cytokine-induced killer cells against multiple myeloma cells after co-culture with idiotype-pulsed dendritic cells. Haematologica 86(10):1029–1037

    CAS  PubMed  Google Scholar 

  114. Cheng XY, Li JL (2015) Biological activity of cytotoxic dendritic cells cocultured with cytokine-induced killer cells and their effect on acute leukemia cells. Genet Mol Res: GMR 14(4):13208–13214. https://doi.org/10.4238/2015.October.26.17

    Article  CAS  PubMed  Google Scholar 

  115. Chan JK, Hamilton CA, Cheung MK, Karimi M, Baker J, Gall JM, Schulz S, Thorne SH, Teng NN, Contag CH, Lum LG, Negrin RS (2006) Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study. Clin Cancer Res 12(6):1859–1867. https://doi.org/10.1158/1078-0432.ccr-05-2019

    Article  CAS  PubMed  Google Scholar 

  116. Du SH, Li Z, Chen C, Tan WK, Chi Z, Kwang TW (2016) Co-expansion of cytokine-induced killer cells and Vgamma9Vdelta2 T cells for CAR T-cell therapy. 11 (9):e0161820. https://doi.org/10.1371/journal.pone.0161820

  117. Poh SL, Linn YC (2016) Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. 65 (5):525-536. https://doi.org/10.1007/s00262-016-1815-8

  118. Laumbacher B, Gu S, Wank R (2012) Activated monocytes prime naive T cells against autologous cancer: vigorous cancer destruction in vitro and in vivo. Scand J Immunol 75(3):314–328. https://doi.org/10.1111/j.1365-3083.2011.02652.x

    Article  CAS  PubMed  Google Scholar 

  119. Wank R, Song X, Gu S, Laumbacher B (2014) Benefits of a continuous therapy for cancer patients with a novel adoptive cell therapy by cascade priming (CAPRI). Immunotherapy 6(3):269–282. https://doi.org/10.2217/imt.14.6

    Article  CAS  PubMed  Google Scholar 

  120. Ikeda H (2016) T-cell adoptive immunotherapy using tumor-infiltrating T cells and genetically engineered TCR-T cells. Int Immunol 28(7):349–353. https://doi.org/10.1093/intimm/dxw022

    Article  CAS  PubMed  Google Scholar 

  121. Geiger TL, Rubnitz JE (2015) New approaches for the immunotherapy of acute myeloid leukemia. Discov Med 19(105):275–284

    PubMed  PubMed Central  Google Scholar 

  122. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517. https://doi.org/10.1056/NEJMoa1407222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6(224):224ra225. https://doi.org/10.1126/scitranslmed.3008226

    Article  CAS  Google Scholar 

  124. Wang QS, Wang Y, Lv HY, Han QW, Fan H, Guo B, Wang LL, Han WD (2015) Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther 23(1):184–191. https://doi.org/10.1038/mt.2014.164

    Article  CAS  PubMed  Google Scholar 

  125. Kenderian SS, Ruella M, Shestova O, Klichinsky M, Aikawa V, Morrissette JJ, Scholler J, Song D, Porter DL, Carroll M, June CH, Gill S (2015) CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 29(8):1637–1647. https://doi.org/10.1038/leu.2015.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hoang T, Foster A, Crisostomo J, Lu A, Moseley A, Heemskerk MHM, Slawin KM, Spencer DM (2015) Inducible MyD88/CD40 enhances proliferation and survival of PRAME-specific TCR-engineered T cells and increases anti-tumor effects in myeloma [abstract]. Blood 126(23):1886

  127. Xue SA, Gao L, Thomas S, Hart DP, Xue JZ, Gillmore R, Voss RH, Morris E, Stauss HJ (2010) Development of a Wilms’ tumor antigen-specific T-cell receptor for clinical trials: engineered patient’s T cells can eliminate autologous leukemia blasts in NOD/SCID mice. Haematologica 95(1):126–134. https://doi.org/10.3324/haematol.2009.006486

    Article  PubMed  CAS  Google Scholar 

  128. Tawara I, Masuya M, Kageyama S, Nishida T, Terakura S, Murata M, Fujiwara H, Akatsuka Y, Ikeda H, Miyahara Y, Tomura D, Nukaya I, Takesako K, Emi N, Yasukawa M, Katayama N, Shiku H (2015) Adoptive transfer of WT1-specific TCR gene-transduced lymphocytes in patients with myelodysplastic syndrome and acute myeloid leukemia [abstract]. Blood 126(23):97

  129. Tanimoto K, Fujiwara H, Tawara I, Masuya M, Kageyama S, Nishida T, Murata M, Terakura S, Akatsuka Y, Ikeda H, Miyahara Y, Nukaya I, Takesako K, Emi N, Katayama N, Shiku H, Yasukawa M (2016) Phase 1 clinical trial of adoptive immunotherapy for acute myelogenous leukemia and myelodysplastic syndrome, using gene-modified autologous lymphocytes expressing WT1-specific T-cell receptor [abstract]. Blood 128(22):1653

  130. Ikeda H, Akahori Y, Yoneyama M, Orito Y, Miyahara Y, Amaishi Y, Okamoto S, Mineno J, Takesako K, Fujiwara H, Yasukawa M, Shiku H (2015) Immunotherapy with chimeric antigen receptor targeting intracellular WT1 gene product complexed with HLA-a*24:02 molecule [abstract]. Blood 126(23):4292

  131. Campillo-Davo D, Fujiki F, Bergh JMJVd, Smits EL, Sugiyama H, Tendeloo VFIV, Berneman ZN (2016) Electroporation of Dicer-substrate siRNA duplexes targeting endogenous TCR enhance tumor killing activity of Wilms’ tumor 1 (WT1)-specific TCR-redirected cytotoxic T cells [abstract]. Blood 128(22):813

  132. Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Honemann D, Gambell P, Westerman DA, Haurat J, Westwood JA, Scott AM, Kravets L, Dickinson M, Trapani JA, Smyth MJ, Darcy PK, Kershaw MH, Prince HM (2013) Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 21(11):2122–2129. https://doi.org/10.1038/mt.2013.154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, Hoffman L, Aguilar B, Chang WC, Bretzlaff W, Chang B, Jonnalagadda M, Starr R, Ostberg JR, Jensen MC, Bhatia R, Forman SJ (2013) T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 122(18):3138–3148. https://doi.org/10.1182/blood-2012-12-474056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, Gentner B, Gullotta F, Ponzoni M, Bernardi M, Marcatti M, Saudemont A, Bordignon C, Savoldo B, Ciceri F, Naldini L, Dotti G, Bonini C, Bondanza A (2013) CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood 122(20):3461–3472. https://doi.org/10.1182/blood-2013-04-493361

    Article  CAS  PubMed  Google Scholar 

  135. Miyazaki Y, Fujiwara H, Asai H, Ochi F, Ochi T, Azuma T, Ishida T, Okamoto S, Mineno J, Kuzushima K, Shiku H, Yasukawa M (2013) Development of a novel redirected T-cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia. Blood 121(24):4894–4901. https://doi.org/10.1182/blood-2012-11-465971

    Article  CAS  PubMed  Google Scholar 

  136. Bigalke I, Honnashagen K, Lundby M, Kasten J, Inderberg EMS, Skoge L, Saboe-Larssen S, Schendel DJ, Kvalheim G (2014) Vaccination with a new generation of fast dendritic cells transfected with mRNA from hTERT, survivin and autologous tumor mount strong immune responses and prolong survival [abstract]. Blood 124(21):2440

  137. Stauss HJ (2017) Turn to TCRs when CARs fail. Oncotarget 8(8):12538–12539. https://doi.org/10.18632/oncotarget.15088

    PubMed  PubMed Central  Google Scholar 

  138. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. LaBelle JL, Hanke CA, Blazar BR, Truitt RL (2002) Negative effect of CTLA-4 on induction of T-cell immunity in vivo to B7-1+, but not B7-2+, murine myelogenous leukemia. Blood 99(6):2146–2153

    Article  CAS  PubMed  Google Scholar 

  141. Fevery S, Billiau AD, Sprangers B, Rutgeerts O, Lenaerts C, Goebels J, Landuyt W, Kasran A, Boon L, Sagaert X, De Wolf-Peeters C, Waer M, Vandenberghe P (2007) CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease. Leukemia 21(7):1451–1459. https://doi.org/10.1038/sj.leu.2404720

    Article  CAS  PubMed  Google Scholar 

  142. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, Rodig SJ, Hirakawa M, Severgnini M, Hodi FS, CJ W, Ho VT, Cutler C, Koreth J, Alyea EP, Antin JH, Armand P, Streicher H, Ball ED, Ritz J, Bashey A, Soiffer RJ (2016) Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 375(2):143–153. https://doi.org/10.1056/NEJMoa1601202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Masarova L, Kantarjian H, Garcia-Mannero G, Ravandi F, Sharma P, Daver N (2017) Harnessing the immune system against leukemia: monoclonal antibodies and checkpoint strategies for AML. Adv Exp Med Biol 995:73–95. https://doi.org/10.1007/978-3-319-53156-4_4

    Article  PubMed  Google Scholar 

  144. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14(12):1212–1218. https://doi.org/10.1038/ni.2762

    Article  CAS  PubMed  Google Scholar 

  145. Kronig H, Kremmler L, Haller B, Englert C, Peschel C, Andreesen R, Blank CU (2014) Interferon-induced programmed death-ligand 1 (PD-L1/B7-H1) expression increases on human acute myeloid leukemia blast cells during treatment. Eur J Haematol 92(3):195–203. https://doi.org/10.1111/ejh.12228

    Article  PubMed  CAS  Google Scholar 

  146. Sehgal A, Whiteside TL, Boyiadzis M (2015) Programmed death-1 checkpoint blockade in acute myeloid leukemia. Expert Opin Biol Ther 15(8):1191–1203. https://doi.org/10.1517/14712598.2015.1051028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A (2008) 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 14(10):3044–3051. https://doi.org/10.1158/1078-0432.ccr-07-4079

    Article  CAS  PubMed  Google Scholar 

  148. Berrien-Elliott MM, Jackson SR, Meyer JM, Rouskey CJ, Nguyen TL, Yagita H, Greenberg PD, DiPaolo RJ, Teague RM (2013) Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance. Cancer Res 73(2):605–616. https://doi.org/10.1158/0008-5472.can-12-2179

    Article  CAS  PubMed  Google Scholar 

  149. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK, Blazar BR (2011) Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117(17):4501–4510. https://doi.org/10.1182/blood-2010-10-310425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, HT W, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368(22):2059–2074. https://doi.org/10.1056/NEJMoa1301689

    Article  PubMed  CAS  Google Scholar 

  151. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447. https://doi.org/10.1182/blood-2016-08-733196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Rotiroti MC, Arcangeli S, Casucci M, Perriello V, Bondanza A, Biondi A, Tettamanti S, Biagi E (2016) Acute myeloid leukemia (AML) targeting by CAR T cells: bridging the gap from preclinical modeling to human studies. Hum Gene Ther. https://doi.org/10.1089/hum.2016.092

  153. Zah E, Lin MY, Silva-Benedict A, Jensen MC, Chen YY (2016) T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res 4(6):498–508. https://doi.org/10.1158/2326-6066.cir-15-0231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Arndt C, Feldmann A, Koristka S, Cartellieri M, Bonin Mv, Ehninger A, Bornhäuser M, Ehninger G, Bachmann MP (2015) Improved killing of AML blasts by dual-targeting of CD123 and CD33 via Unitarg a novel antibody-based modular T cell retargeting system [abstract]. Blood 126(23):2565

  155. Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, June CH, Schuster SJ (2017) PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129(8):1039–1041. https://doi.org/10.1182/blood-2016-09-738245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Municipal Science and Technology Bureau of Nanjing under Grant (YKK13116).

Author information

Authors and Affiliations

  1. Department of Hematology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu, People’s Republic of China

    Dan Yang, Xiuqun Zhang, Xuezhong Zhang & Yanli Xu

Authors
  1. Dan Yang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Xiuqun Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Xuezhong Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Yanli Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Yanli Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, D., Zhang, X., Zhang, X. et al. The progress and current status of immunotherapy in acute myeloid leukemia. Ann Hematol 96, 1965–1982 (2017). https://doi.org/10.1007/s00277-017-3148-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-017-3148-x

Keywords