Skip to main content
SpringerLink
Log in
Book cover

Immunotherapy pp 97–116Cite as

Update on Immunotherapy in AML and MDS: Monoclonal Antibodies and Checkpoint Inhibitors Paving the Road for Clinical Practice

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 995))

Abstract

In the past few years, our improved understanding of the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has led to remarkable advances in the development of novel therapeutic approaches for these diseases. This chapter summarizes the available clinical data with immune-based therapeutic modalities in AML and MDS, focusing on monoclonal antibodies, T cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD-1/PD-L1 or CTLA4. Numerous clinical trials are currently ongoing in patients with AML and MDS, both in the frontline and relapsed refractory setting. Given the natural diversity of AML blasts, it became apparent that the best responses would be achieved with rationally designed combination strategies of immune therapy, molecular therapy, and chemotherapy. A number of such combinations are enrolling patients with AML in various clinical settings. Biomarkers to select the optimal combination regimen for individual patients are critical.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973;57:485–8.

    CAS  PubMed  Google Scholar 

  2. Kantarjian HM. Therapy for elderly patients with acute myeloid leukemia: a problem in search of solutions. Cancer. 2007;109:1007–10. https://doi.org/10.1002/cncr.22502.

    Article  CAS  PubMed  Google Scholar 

  3. Saito Y, et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med. 2010;2:17ra19. https://doi.org/10.1126/scitranslmed.3000349.

    Article  CAS  Google Scholar 

  4. Hauswirth AW, et al. Expression of the target receptor CD33 in CD34+/CD38-/CD123+ AML stem cells. Eur J Clin Invest. 2007;37:73–82. https://doi.org/10.1111/j.1365-2362.2007.01746.x.

    Article  CAS  PubMed  Google Scholar 

  5. Larson RA, et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005;104:1442–52. https://doi.org/10.1002/cncr.21326.

    Article  CAS  PubMed  Google Scholar 

  6. Sievers EL, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19:3244–54.

    Article  CAS  Google Scholar 

  7. Petersdorf SH, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121:4854–60. https://doi.org/10.1182/blood-2013-01-466706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Burnett AK, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29:369–77. https://doi.org/10.1200/jco.2010.31.4310.

    Article  CAS  PubMed  Google Scholar 

  9. Burnett AK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30:3924–31. https://doi.org/10.1200/jco.2012.42.2964.

    Article  CAS  PubMed  Google Scholar 

  10. Castaigne S, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379:1508–16. https://doi.org/10.1016/s0140-6736(12)60485-1.

    Article  CAS  Google Scholar 

  11. Amadori S, et al. 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. J Clin Oncol. 2016;34:972–9. https://doi.org/10.1200/jco.2015.64.0060.

    Article  PubMed  Google Scholar 

  12. Taksin AL, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007;21:66–71. https://doi.org/10.1038/sj.leu.2404434.

    Article  CAS  PubMed  Google Scholar 

  13. Kung Sutherland MS, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013;122:1455–63. https://doi.org/10.1182/blood-2013-03-491506.

    Article  CAS  PubMed  Google Scholar 

  14. Sutherland MK, et al. 5-azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia. MAbs. 2010;2:440–8.

    Article  Google Scholar 

  15. Stein EM, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131:387–96. https://doi.org/10.1182/blood-2017-06-789800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Erba HP, Levy MY, Vasu S, et al. A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Blood. 2016;128:211. Abstract 906

    Google Scholar 

  17. Fathi AT, Erba HP, Lancet JE, et al. Vadastuximab talirine plus hypomethylating agents: a well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia. Leukemia. 2016;128(22):591.

    Google Scholar 

  18. Bothell W. Seattle genetics. 2017.

    Google Scholar 

  19. Watkins K, Walker R Fishkin N, Audette C, Kovtun Y, Romanelli A. 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. Blood. 2015;126. Abstract No 1366.

    Google Scholar 

  20. Whiteman KR, Noordhuis P Walker R, Watkins K, Kovtun Y, Harvey L, Wilhelm A, et al. The antibody-drug conjugate (ADC) IMGN779 is highly active in vitro and in vivo against acute myeloid leukemia (AML) with FLT3-ITD mutations. Blood. 2014. Abstract No 2321.

    Google Scholar 

  21. Adams S, Watkins K, McCarthy R, Wilhelm A, et al. IMGN779, a next generation CD33-targeting ADC, combines effectively with cytarabine in acute myeloid leukemia (AML) preclinical models, resulting in increased DNA damage response, cell cycle arrest and apoptosis in vitro and prolonged survival in vivo. Blood. 2017;130:1357.

    Article  Google Scholar 

  22. Cortes J, Traer E, Wang E, Erba HP, et al. IMGN779, a next-generation CD33-targeting antibody-drug conjugate (ADC) demonstrates initial antileukemia activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2017;130:1312.

    Google Scholar 

  23. Bagley CJ, Woodcock JM, Stomski FC, Lopez AF. The structural and functional basis of cytokine receptor activation: lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors. Blood. 1997;89:1471–82.

    CAS  PubMed  Google Scholar 

  24. Testa U, et al. Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood. 2002;100:2980–8. https://doi.org/10.1182/blood-2002-03-0852.

    Article  CAS  PubMed  Google Scholar 

  25. Smith BD, Roboz GJ, Walter RB, et al. 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. Blood. 2014. Abstract 616.

    Google Scholar 

  26. Frankel AE, Ramage J, Kiser M, Alexander R, Kucera G, Miller MS. Characterization of diphtheria fusion proteins targeted to the human interleukin-3 receptor. Protein Eng. 2000;13:575–81.

    Article  CAS  Google Scholar 

  27. Pemmaraju N, Sweet KL, Lane AA, Stein AS, et al. Results of pivotal phase 2 trial of SL-401 in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood. 2017;130:1298.

    Google Scholar 

  28. Frankel AE, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood. 2014;124:385–92. https://doi.org/10.1182/blood-2014-04-566737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Konopleva M, Hogge DE, Rizzieri D, Cirrito T, Liu JS, Kornblau S, Grable M, Hwang IL, Borthakur G, et al. Phase I trial results for SL-401, a novel cancer stem cell (CSC) targeting agent, demonstrate clinical efficacy at tolerable doses in patients with heavily pre-treated AML, poor risk elderly AML, and high risk MDS. In: 53th ASH Annual Meeting and Exposition Abstract No 3298; 2010.

    Google Scholar 

  30. Sweet K, Pemmaraju N, Lane A, Stein A, Vasu S, Blum W, Rizzieri DA, et al. 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). Blood. 2015;126. Abstract No 3795.

    Google Scholar 

  31. Lane AA, Sweet KL, Wang ES, et al. Results from ongoing phase 2 trial of SL-401 as consolidation therapy in patients with acute myeloid leukemia (AML) in remission with high relapse risk including minimal residual disease (MRD). Blood. 2016;128:215.

    Google Scholar 

  32. Stephansky J, Togami K, Ghandi M, Montero J, et al. Resistance to SL-401 in AML and BPDCN is associated with loss of the diphthamide synthesis pathway enzyme DPH1 and is reversible by azacitidine. Blood. 2017;130:797.

    Google Scholar 

  33. Romagne F, Andre P, Spee P et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 2009;114:2667–2677.

    Google Scholar 

  34. Vey N, Dumas P-Y, Recher C, Gastaud L, et al. Randomized phase 2 trial of lirilumab (anti-KIR monoclonal antibody, mAb) as maintenance treatment in elderly patients (pts) with acute myeloid leukemia (AML): Results of the Effikir Trial. Blood. 2017;130:889.

    Google Scholar 

  35. Daver N, Boddu P, Garcia-Manero G, Ravandi F, et al. Phase IB/II study of lirilumab with azacytidine (AZA) in relapsed AML. Blood. 2017;130:2634.

    Google Scholar 

  36. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69:4941–4. https://doi.org/10.1158/0008-5472.can-09-0547.

    Article  CAS  PubMed  Google Scholar 

  37. Cheng P, Eksioglu E, Chen X, et al. Immunodepletion of MDSC By AMV564, a novel tetravalent bispecific CD33/CD3 T cell engager restores immune homeostasis in MDS in vitro. Blood. 2017;130:51.

    Google Scholar 

  38. Mougiakakos D, Saul D, Braun M, et al. CD33/CD3-bispecific T-cell engaging (BiTE®) antibody constructs efficiently target monocytic CD14+ hla-DRlow IDO+ aml-MDSCs. Blood. 2017;130:1363.

    Google Scholar 

  39. Vallera DA, et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin Cancer Res. 2016;22:3440–50. https://doi.org/10.1158/1078-0432.ccr-15-2710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rader C. DARTs take aim at BiTEs. Blood. 2011;117:4403–4. https://doi.org/10.1182/blood-2011-02-337691.

    Article  CAS  PubMed  Google Scholar 

  41. Chichili GR, et al. A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci Transl Med. 2015;7:289ra282. https://doi.org/10.1126/scitranslmed.aaa5693.

    Article  CAS  Google Scholar 

  42. Uy GL, Godwin J, Rettig PM, et al. Preliminary results of a phase 1 study of flotetuzumab, a CD123 × CD3 Bispecific Dart® protein, in patients with relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. Blood. 2017;130:637.

    Google Scholar 

  43. Jacobs K, Godwin J, Foster M, Vey N, et al. Lead-in dose optimization to mitigate cytokine release syndrome in AML and MDS patients treated with flotetuzumab, a CD123 × CD3 Dart® molecule for T-cell redirected therapy. Blood. 2017;130:3856.

    Google Scholar 

  44. Rettig M, Godwin J, Vey N, Fox B, et al. Preliminary translational results from an ongoing phase 1 study of flotetuzumab, a CD123 × CD3 Dart®, in AML/MDS: rationale for combining flotetuzumab and anti-PD-1/PD-L1 immunotherapies. Blood. 2017;130:1365.

    Google Scholar 

  45. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–8. https://doi.org/10.1126/science.aaa4967.

    Article  CAS  PubMed  Google Scholar 

  46. Pegram HJ, Park JH, Brentjens RJ. CD28z CARs and armored CARs. Cancer J. 2014;20:127–33. https://doi.org/10.1097/ppo.0000000000000034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ritchie DS, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther. 2013;21:2122–9. https://doi.org/10.1038/mt.2013.154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Budde L, Song JY, Blanhcard S, Wagner J, et al. Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: a first-in-human clinical trial. Blood. 2017;130:811.

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang XY, Zeng H, Chen FP. Cytokine-induced killer cells: a novel immunotherapy strategy for leukemia. Oncol Lett. 2015;9:535–41. https://doi.org/10.3892/ol.2014.2780.

    Article  PubMed  Google Scholar 

  51. Zhang X, Yang J, Zhang G, Lu P. A 11-year clinical summary of DC—CIK/NK cell immunotherapy for 152 patients with acute myeloid leukemia. Blood. 2017;130:1369.

    Google Scholar 

  52. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fevery S, et al. CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease. Leukemia. 2007;21:1451–9. https://doi.org/10.1038/sj.leu.2404720.

    Article  CAS  PubMed  Google Scholar 

  54. Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114:1528–36. https://doi.org/10.1182/blood-2008-09-179697.

    Article  CAS  PubMed  Google Scholar 

  55. 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. https://doi.org/10.1182/blood-2009-03-206672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhou Q, 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. https://doi.org/10.1182/blood-2010-10-310425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Williams P, Basu S, Garcia-Manero G, Cortes J, et al. Checkpoint expression by acute myeloid leukemia (AML) and the immune microenvironment suppresses adaptive immunity. Blood. 2017;130:185.

    Google Scholar 

  58. Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol. 2015;6:29. https://doi.org/10.3389/fimmu.2015.00029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yang H, 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(6):1280–8. https://doi.org/10.1038/leu.2013.355.

    Article  CAS  PubMed  Google Scholar 

  60. Davids MS, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143–53. https://doi.org/10.1056/NEJMoa1601202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Davids MS, Kim HT, Costello C, Herrera AF, et al. Optimizing checkpoint blockade as a treatment for relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Blood. 2017;130:275.

    Article  Google Scholar 

  62. Garcia-Manero G, Daver NG, Montalban-Bravo G, Jabbour EJ, et al. A phase II study evaluating the combination of nivolumab (Nivo) or ipilimumab (Ipi) with azacitidine in Pts with previously treated or untreated myelodysplastic syndromes (MDS). Blood. 2016;128:344.

    Google Scholar 

  63. Daver N, Basu S, Garcia-Manero G, Cortes EJ, et al. Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed AML. J Clin Oncol. 2017;35:7026–702.

    Article  Google Scholar 

  64. Ravandi F, Daver N, Garcia-Manero G, Benton CB, et al. Phase 2 study of combination of cytarabine, idarubicin, and nivolumab for initial therapy of patients with newly diagnosed acute myeloid leukemia. Blood. 2017;130:815.

    Google Scholar 

  65. Zeidner FJ, Vincent BG, Ivanova A, Foster M, et al. Phase II study of high dose cytarabine followed by pembrolizumab in relapsed/refractory acute myeloid leukemia (AML). Blood. 2017;130:1349.

    Google Scholar 

Download references

Funding Source

This review was supported in part by the MD Anderson Cancer Center Support Grant (CCSG) CA016672.

Conflict of Interest L.M. and G.G.M.—none. N.D.—research funding from BMS, Pfizer, Immunogen, AbbVie, Astellas, Servier, Daiichi-Sankyo, Nohla, Genentech; advisor/consultant to Novartis, BMS, Daiichi-Sankyo, Astellas, AbbVie, Pfizer, Jazz, Agios, and Celgene. H.K.—research grants from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, Pfizer; honoraria: AbbVie, Actinium (advisory board), Agios, Amgen, Immunogen, Orsinex, Pfizer, Takeda. F.R.—research support and honoraria from BMS. P.S.—stock/ownership for Jounce, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak; advisory board on Constellation, Jounce, Kite Pharma, Neon, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck, BioMx, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak.

Author information

Authors and Affiliations

  1. Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA

    Lucia Masarova, Hagop Kantarjian, Farhad Ravandi, Guillermo Garcia-Manero & Naval Daver

  2. Department of Immunotherapy Platform, MD Anderson Cancer Center, Houston, TX, USA

    Padmanee Sharma

Authors
  1. Lucia Masarova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hagop Kantarjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Farhad Ravandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Padmanee Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guillermo Garcia-Manero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naval Daver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naval Daver .

Editor information

Editors and Affiliations

  1. MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    Aung Naing

  2. Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    Joud Hajjar

Additional information

Lucia Masarova and Naval Daver collected and reviewed the data and wrote the paper. All authors participated in the discussion, have reviewed and approved the current version of the manuscript.

Naval Daver is responsible for the overall content as guarantor.

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Masarova, L., Kantarjian, H., Ravandi, F., Sharma, P., Garcia-Manero, G., Daver, N. (2018). Update on Immunotherapy in AML and MDS: Monoclonal Antibodies and Checkpoint Inhibitors Paving the Road for Clinical Practice. In: Naing, A., Hajjar, J. (eds) Immunotherapy. Advances in Experimental Medicine and Biology, vol 995. Springer, Cham. https://doi.org/10.1007/978-3-030-02505-2_4

Download citation

Publish with us

Policies and ethics

Search

Navigation