Abstract
Precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) affects hematopoietic development and therefore is associated with immune deficiencies that can be further exacerbated by chemotherapy. It is unclear if and when monoclonal antibodies (mAbs) that stimulate antibody-mediated cellular cytotoxicity (ADCC) can be used for treatment because this depends on the presence of functional effector cells. Here, we used flow cytometry to determine that patient samples at diagnosis, post-induction and relapse contain detectable numbers of CD56+ cells. We were able to selectively expand CD56+ immune effector cells from bone marrow and peripheral blood samples at diagnosis and at various stages of treatment by co-culture with artificial antigen-presenting K562 clone 9.mbIL-21 cells. Amplified CD56+CD3− cells had spontaneous and anti-B cell-activating factor receptor mAb-stimulated ADCC activity against allogeneic ALL cells, which could be further enhanced by IL-15. Importantly, matched CD56+ effector cells also killed autologous ALL cells grown out from leukemia samples of the same patient, through both spontaneous as well as antibody-dependent cellular cytotoxicity. Since autologous cell therapy will not be complicated by graft-versus-host disease, our results show that expanded CD56+ cells could be applied for treatment of pre-B ALL without transplantation, or for purging of bone marrow in the setting of autologous bone marrow transplants.
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References
Haining WN, Cardoso AA, Keczkemethy HL, Fleming M, Neuberg D, DeAngelo DJ et al. Failure to define window of time for autologous tumor vaccination in patients with newly diagnosed or relapsed acute lymphoblastic leukemia. Exp Hematol 2005; 33: 286–294.
Shah NN, Dave H, Wayne AS . Immunotherapy for pediatric leukemia. Front Oncol 2013; 3: 166.
Verheyden S, Demanet C . NK cell receptors and their ligands in leukemia. Leukemia 2008; 22: 249–257.
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.
Stojanovic A, Correia MP, Cerwenka A . Shaping of NK cell responses by the tumor microenvironment. Cancer Microenviron 2013; 6: 135–146.
Fujisaki H, Kakuda H, Imai C, Mullighan CG, Campana D . Replicative potential of human natural killer cells. Br J Haematol 2009; 145: 606–613.
Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res 2009; 69: 4010–4017.
Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One 2012; 7: e30264.
Liu Y, Wu HW, Sheard MA, Sposto R, Somanchi SS, Cooper LJ et al. Growth and activation of natural killer cells ex vivo from children with neuroblastoma for adoptive cell therapy. Clin Cancer Res 2013; 19: 2132–2143.
Matlawska-Wasowska K, Ward E, Stevens S, Wang Y, Herbst R, Winter SS et al. Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies. Leukemia 2013; 27: 1263–1274.
Kellner C, Zhukovsky EA, Potzke A, Bruggemann M, Schrauder A, Schrappe M et al. The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cell-mediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients. Leukemia 2013; 27: 1595–1598.
Kantarjian H, Thomas D, Wayne AS, O'Brien S . Monoclonal antibody-based therapies: a new dawn in the treatment of acute lymphoblastic leukemia. J Clin Oncol 2012; 30: 3876–3883.
Parameswaran R, Lim M, Fei F, Abdel-Azim H, Arutyunyan A, Schiffer I et al. Effector-mediated eradication of precursor B acute lymphoblastic leukemia with a novel Fc-engineered monoclonal antibody targeting the BAFF-R. Mol Cancer Ther 2014; 13: 1567–1577.
Fei F, Stoddart S, Groffen J, Heisterkamp N . Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias. Mol Cancer Ther 2010; 9: 1318–1327.
Alter G, Malenfant JM, Altfeld M . CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 2004; 294: 15–22.
Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013; 121: 3599–3608.
Drexler HG . Establishment and culture of leukemia-lymphoma cell lines. Methods Mol Biol 2011; 731: 181–200.
Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, Klemm L et al. Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood 2011; 118: 2191–2199.
Parameswaran R, Muschen M, Kim YM, Groffen J, Heisterkamp N . A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias. Cancer Res 2010; 70: 4346–4356.
Imamura M, Shook D, Kamiya T, Shimasaki N, Chai SM, Coustan-Smith E et al. Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 2014; 124: 1081–1088.
Cany J, van der Waart AB, Tordoir M, Franssen GM, Hangalapura BN, de Vries J et al. Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rg(null) mice. PLoS One 2013; 8: e64384.
Alanko S, Salmi TT, Pelliniemi TT . Recovery of natural killer cells after chemotherapy for childhood acute lymphoblastic leukemia and solid tumors. Med Pediatr Oncol 1995; 24: 373–378.
Wang Y, Bo J, Dai HR, Lu XC, Lv HY, Yang B et al. CIK cells from recurrent or refractory AML patients can be efficiently expanded in vitro and used for reduction of leukemic blasts in vivo. Exp Hematol 2013; 41: 241–252 e243.
Pievani A, Borleri G, Pende D, Moretta L, Rambaldi A, Golay J et al. Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. Blood 2011; 118: 3301–3310.
Jakel CE, Schmidt-Wolf IG . An update on new adoptive immunotherapy strategies for solid tumors with cytokine-induced killer cells. Expert Opin Biol Ther 2014; 14: 905–916.
Fujii S, Shimizu K, Okamoto Y, Kunii N, Nakayama T, Motohashi S et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front Immunol 2013; 4: 409.
Beum PV, Lindorfer MA, Taylor RP . Within peripheral blood mononuclear cells, antibody-dependent cellular cytotoxicity of rituximab-opsonized Daudi cells is promoted by NK cells and inhibited by monocytes due to shaving. J Immunol 2008; 181: 2916–2924.
Locatelli F, Moretta F, Brescia L, Merli P . Natural killer cells in the treatment of high-risk acute leukaemia. Semin Immunol 2014; 26: 173–179.
Childs RW, Berg M . Bringing natural killer cells to the clinic: ex vivo manipulation. Hematology Am Soc Hematol Educ Program 2013; 2013: 234–246.
Campbell KS, Hasegawa J . Natural killer cell biology: an update and future directions. J Allergy Clin Immunol 2013; 132: 536–544.
Sun JC . Re-educating natural killer cells. J Exp Med 2010; 207: 2049–2052.
Hombach AA, Rappl G, Abken H . Arming cytokine-induced killer cells with chimeric antigen receptors: CD28 outperforms combined CD28-OX40 ‘super-stimulation’. Mol Ther 2013; 21: 2268–2277.
Acknowledgements
We thank Patty Bacilio for initial involvement in expanding CD56+ cells from normal PBMC. This study was supported by grants from Alex’s Lemonade Stand Foundation, the Leukemia & Lymphoma Society, the V-Foundation and PHS grants CA090321 and CA174020 (NH).
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DL is recipient of a Scholar Award from the St. Baldrick’s Foundation.
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Fei, F., Lim, M., George, A. et al. Cytotoxicity of CD56-positive lymphocytes against autologous B-cell precursor acute lymphoblastic leukemia cells. Leukemia 29, 788–797 (2015). https://doi.org/10.1038/leu.2014.246
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DOI: https://doi.org/10.1038/leu.2014.246
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