T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease linked to a broad spectrum of molecular alterations, and as such, long-term disease control requires multiple therapeutic approaches. Driven largely by an improved understanding and targeting of these molecular aberrations, AML treatment has rapidly evolved over the last 3–5 years. The stellar successes of immunotherapies that harness the power of T cells to treat solid tumors and an improved understanding of the immune systems of patients with hematologic malignancies have led to major efforts to develop immunotherapies for the treatment of patients with AML. Several immunotherapies that harness T cells against AML are in various stages of preclinical and clinical development. These include bispecific and dual antigen receptor-targeting antibodies (targeted to CD33, CD123, CLL-1, and others), chimeric antigen receptor (CAR) T-cell therapies, and T-cell immune checkpoint inhibitors (including those targeting PD-1, PD-L1, CTLA-4, and newer targets such as TIM3 and STING). The current and future directions of these T-cell-based immunotherapies in the treatment landscape of AML are discussed in this review.

References 125

1. 1.

   Schmid C, Labopin M, Schaap N, Veelken H, Schleuning M, Stadler M, et al. Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia—a matched pair analysis by the Acute Leukaemia Working Party of EBMT. Br J Haematol. 2019;184:782-7.

   Not in our library

2. 2.

   Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836-47.

   Not in our library10.1056/nejmoa1609783

3. 3.

   Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522-31.

   Not in our library10.1182/blood-2017-08-798322

4. 4.

   Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-48.

   Not in our library10.1056/nejm1709866

5. 5.

   Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-44.

   Not in our library10.1056/nejmmoa1707447

6. 6.

   Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56.

   Not in our library10.1056/nejmoa1804980

7. 7.

   Armand P, Engert P, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial. J Clin Oncol. 2018;36:1428-39.

   Not in our library10.1200/jco.2017.76.0793

8. 8.

   Chen R, Zinzani PL, Lee HJ, Armand P, Johnson NA, Brice P, et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood. 2019;134:1144-53.

   Not in our library10.1182/blood.2019000324

9. 9.

   Armand P, Rodig S, Melnichenko V, Theiblemont C, Bouabdallah K, Tumyan G, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol. 2019;37:3291-9.

   Not in our library10.1200/jco.19.01389

10. 10.
    Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML · 2018

    No notice
11. 11.

    Tawara I, Kageyama S, Miyahara Y, Fujiwara H, Nishida T, Akatsuka Y, et al. Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS. Blood. 2017;130:1985-94.

    Not in our library10.1182/blood-2017-06-791202

12. 12.

    Anguille S, Van de Velde AL, Smits EL, Van Tendeloo VF, Juliusson G, Cools N, et al. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood. 2017;130:1713-21.

    Not in our library10.1182/blood-2017-04-780155

13. 13.

    Lichtenegger FS, Schnorfeil FM, Rothe M, Deiser K, Altmann T, Bücklein VL, et al. Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: Results of a phase I trial. Clin Transl Immunol. 2020;9:e1117.

    Not in our library10.1002/cti2.1117

14. 14.

    Perna F, Berman SH, Soni RK, Mansilla-Soto J, Eyquem J, Hamieh M, et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell. 2017;32:506-19.e5.

    Not in our library10.1016/j.ccell.2017.09.004

15. 15.

    Koehnke T, Xilong L, Haubner S, Krupka C, Solis-Mezarino V, Herzog F, et al. Identification of novel targets for antibody or chimeric antigen receptor (CAR) based immunotherapy in AML: characterizing the surfaceome from primary patient samples. Blood. 2017;130(Supplement 1):3968.

    Not in our library

16. 16.

    Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, et al. Genetic mechanisms of target antigen loss in CD19 therapy of acute lymphoblastic leukemia. Nat Med. 2018;24:1504-6.

    Not in our library10.1038/s41591-018-0146-z

17. 17.

    Majzner RG, Mackall CL. Clinical lessons learned from the first leg of the CAR T cell journey. Nat Med. 2019;25:1341-55.

    Not in our library10.1038/s41591-019-0564-6

18. 18.

    Brinkmann U, Kontermann RE. The making of bispecific antibodies. mAbs. 2017;9:182-212.

    Not in our library10.1080/19420862.2016.1268307

19. 19.

    Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585-608.

    Not in our library10.1038/s41573-019-0028-1

20. 20.

    Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie J-N, 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.

    Not in our library10.1016/s0140-6736(12)60485-1

21. 21.

    Borthakur G, Cortes J, Ravandi F, Garcia-Manero G, Kadia TM, Jabbour E, et al. Fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) regimen results in better molecular response and relapse-free survival in core binding factor acute myeloid leukemia than FLAG and idarubicin (FLAG-Ida). Blood. 2019;134:290.

    Not in our library10.1182/blood-2019-126014

22. 22.

    Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, 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.

    Not in our library10.1200/jco.2010.31.4310

23. 23.

    Hills RK, Castaigne SH, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15:986-96.

    Not in our library10.1016/s1470-2045(14)70281-5

24. 24.

    Krupka C, Kufer P, Kischel R, Zugmaier G, Bögeholz J, Köhnke T, et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood. 2014;123:356-65.

    Not in our library10.1182/blood-2013-08-523548

25. 25.

    Ravandi F, Walter RB, Subklewe M, Buecklein V, Jongen-Lavrencic M, Paschka P, et al. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). J Clin Oncol. 2020;38:7508.

    Not in our library10.1200/jco.2020.38.15_suppl.7508

26. 26.

    Subklewe M, Stein A, Walter RB, Bhatia R, Wei AH, Ritchie D, et al. Preliminary results from a phase 1 first-in-human study of AMG 673, a novel half-life extended (HLE) anti-CD33/CD3 BiTE (bispecific T-cell engager) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Blood. 2019;134(Supplement_1):833.

    Not in our library10.1182/blood-2019-127977

27. 27.

    Subklewe M, Stein A, Walter RB, Bhatia R, Wei AH, Ritchie D, et al. Updated results from a phase 1 first-in-human dose escalation study of AMG 673, a novel anti-CD33/CD3 BiTE® (bispecific T-cell engager) in patients with relapsed/refractory acute myeloid leukemia. European Hematology Association. 2020;Abstract:EP548.

    Not in our library

28. 28.

    Westervelt P, Cortes JE, Altman JK, Long M, Oehler VG, Gojo I, et al. Phase 1 first-in-human trial of AMV564, a bivalent bispecific (2:2) CD33/CD3 T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML). Blood. 2019;134(Supplement_1):834.

    Not in our library10.1182/blood-2019-129042

29. 29.

    Sato N, Caux C, Kitamura T, Watanabe Y, Arai K, Banchereau J, et al. Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells. Blood. 1993;82:752-61.

    Not in our library10.1182/blood.v82.3.752.752

30. 30.

    Jordan CT, Upchurch D, Szilvassay SJ, Guzman ML, Howard DS, Pettigrew AL, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14:1777-84.

    Not in our library10.1038/sj.leu.2401903

31. 31.

    Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, et al. Elevated expression of IL-3Rα in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood. 2002;100:2980-8.

    Not in our library10.1182/blood-2002-03-0852

32. 32.

    Moshaver B, van Rhenen A, Kelder A, van der Pol M, Terwijn M, Bachas C, et al. Identification of a small subpopulation of candidate leukemia‐initiating cells in the side population of patients with acute myeloid leukemia. Stem Cells. 2009;26:3059-67.

    Not in our library10.1634/stemcells.2007-0861

33. 33.

    Campagne O, Delmas A, Fouliard S, Chenel M, Chichili GR, Li H, et al. Integrated pharmacokinetic/pharmacodynamic model of a bispecific CD3xCD123 DART molecule in nonhuman primates: Evaluation of activity and impact of immunogenicity. Clin Cancer Res. 2018;24:2631-41.

    Not in our library10.1158/1078-0432.ccr-17-2265

34. 34.

    Uy GL, Rettig MP, Vey N, Godwin J, Foster MC, Rizzieri DA, et al. Phase 1 cohort expansion of flotetuzumab, a CD123×CD3 bispecific dart protein in patients with relapsed/refractory acute myeloid leukemia (AML). Blood. 2018;132(Supplement 1):764.

    Not in our library10.1182/blood-2018-99-117085

35. 35.

    Uy GL, Aldoss I, Foster MC, Sayre PH, Wieduwilt MJ, Advani AS, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137:751-62.

    Not in our library10.1182/blood.2020007732

36. 36.

    Vadakekolathu J, Lai C, Reeder S, Church SE, Hood T, Lourdusamy A, et al. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood. Adv. 2020;4:5011-24.

    Not in our library10.1182/bloodadvances.2020002512

37. 37.

    Ravandi F, Bashey A, Foran JM, Stock W, Mawad R, Blum W, et al. Complete responses in relapsed/refractory acute myeloid leukemia (AML) patients on a weekly dosing schedule of XmAb14045, a CD123 x CD3 T cell-engaging bispecific antibody: Initial results of a phase 1 study. Blood. 2018;132(Supplement 1):763.

    Not in our library10.1182/blood-2018-99-119786

38. 38.

    van Loo PF, Hangalapura BN, Thordardottir S, Gibbins JD, Veninga H, Hendriks LJA, et al. MCLA-117, a CLEC12AxCD3 bispecific antibody targeting a leukaemic stem cell antigen, induces T cell-mediated AML blast lysis. Expert Opin Biol Ther. 2019;19:721-33.

    Not in our library10.1080/14712598.2019.1623200

39. 39.

    Morsink LM, Walter RB, Ossenkoppele GJ. Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia. Blood Rev. 2018;34:26-33.

    Not in our library10.1016/j.blre.2018.10.003

40. 40.

    Wang Y-Y, Chen W-L, Weng X-Q, Sheng Y, Wu J, Hao J, et al. Low CLL-1 expression is a novel adverse predictor in 123 patients with de novo CD34+ acute myeloid leukemia. Stem Cells Dev. 2017;26:1460-7.

    Not in our library10.1089/scd.2016.0310

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