Infusion of allogeneic natural killer cells in a patient with acute myeloid leukemia in relapse after haploidentical hematopoietic stem cell transplantation
Corresponding Author
Stéphanie Nguyen
Stephanie Nguyen, MD, PhD, Service d'Hématologie Clinique, Pavillon de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, 83-89 Boulevard de l'Hôpital, 75013, Paris, France; e-mail: [email protected]. Search for more papers by this authorVivien Béziat
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorFrançoise Norol
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorMadalina Uzunov
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorHélène Trebeden-Negre
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorNabih Azar
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorAli Boudifa
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorDominique Bories
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorPatrice Debré
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorJean-Paul Vernant
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorVincent Vieillard
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorNathalie Dhédin
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorCorresponding Author
Stéphanie Nguyen
Stephanie Nguyen, MD, PhD, Service d'Hématologie Clinique, Pavillon de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, 83-89 Boulevard de l'Hôpital, 75013, Paris, France; e-mail: [email protected]. Search for more papers by this authorVivien Béziat
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorFrançoise Norol
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorMadalina Uzunov
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorHélène Trebeden-Negre
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorNabih Azar
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorAli Boudifa
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorDominique Bories
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorPatrice Debré
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorJean-Paul Vernant
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorVincent Vieillard
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorNathalie Dhédin
From the Service d'Hématologie Clinique, Service de Thérapie Cellulaire, and the Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris; INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, UPMC, Université Paris-6, Paris; and the Unité d'Hématologie Moléculaire, Hôpital Henri Mondor, Créteil, France.
Search for more papers by this authorSupported by grant from the Association Laurette Fugain and the Agence de la Biomedecine. SN was supported by a fellowship from the Fondation de France and the PARI prize (Prix Amgen pour la Recherche et l'Innovation en thérapie cellulaire).
Abstract
BACKGROUND: Allogeneic donor natural killer (NK)-cell infusion (NK-DLI) is a promising immunotherapy for patients with hematologic disorders.
CASE REPORT: This report describes the case of a patient who received a single haploidentical NK-DLI for a relapse of acute myeloid leukemia (AML) after haploidentical hematopoietic stem cell transplantation. He underwent a cytoreductive, immunosuppressive regimen before NK-DLI and received high-dose interleukin-2 in vivo for 8 weeks afterward.
RESULTS: No major adverse effect was observed. Prospective phenotypic and functional studies of the NK cells showed major expansion of infused NK cells and, more importantly, of the alloreactive KIR2DL1+KIR2DL2/DL3–NKG2A– subset, which reached 117 × 106 cells/L on Day +14 after NK-DLI, the greatest expansion of infused alloreactive NK cells reported so far. Infused NK cells conserved their lytic capacities against K562 target cells and primary AML-mismatched blasts.
CONCLUSION: We review the literature to clarify these data and to detail the indications for allogeneic NK-DLI, the criteria for determining the most suitable donor, the types of conditioning regimens, and the procedures for selecting and activating NK cells.
REFERENCES
- 1 Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097-100.
- 2 Nguyen S, Dhedin N, Vernant JP, Kuentz M, Al Jijakli A, Rouas-Freiss N, Carosella ED, Boudifa A, Debre P, Vieillard V. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood 2005; 105: 4135-42.
- 3 Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S, Lupo Stanghellini MT, Mazzi B, Perna SK, Bondanza A, Middleton D, Palini A, Bernardi M, Bacchetta R, Peccatori J, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation. Blood 2008; 112: 3488-99.
- 4 Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, Bell T, Pui CH, Leung W. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 2010; 28: 955-9.
- 5 Lanier LL. NK cell recognition. Annu Rev Immunol 2005; 23: 225-74.
- 6 Braud VM, Allan DS, O'Callaghan CA, Söderström K, D'Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998; 391: 795-9.
- 7 Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L. Analysis of the receptor-ligand interactions in the NK-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias. Evidence for the involvement of the poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 2004; 105: 2066-73.
- 8 Fauriat C, Andersson S, Björklund AT, Carlsten M, Schaffer M, Björkström NK, Baumann BC, Michaëlsson J, Ljunggren HG, Malmberg KJ. Estimation of the size of the alloreactive NK cell repertoire: studies in individuals homozygous for the group A KIR haplotype. J Immunol 2008; 181: 6010-9.
- 9 Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K, Urbani E, Negrin RS, Martelli MF, Velardi A. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem-cell transplantation. Blood 1999; 94: 333-9.
- 10 Moretta A, Bottino C, Pende D, Tripodi G, Tambussi G, Viale O, Orengo A, Barbaresi M, Merli A, Ciccone E, Moretta L. Identification of four subsets of human CD3-CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J Exp Med 1990; 172: 1589-98.
- 11 Alizadeh M, Bernard M, Dania B, Durian C, Brabant B, Apart C, Limy T, Le Pries PY, Beau A, Bories D, Semana G, Quelvennec E. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood 2002; 99: 4618-25.
- 12 Ljunggren HG, Malmberg KJ. Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 2007; 7: 329-39.
- 13 Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447-54.
- 14 Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, Stern M, Pende D, Perruccio K, Burchielli E, Topini F, Bianchi E, Aversa F, Martelli MF, Velardi A. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 2007; 110: 433-40.
- 15 Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105: 3051-7.
- 16 Shi J, Tricot G, Szmania S, Rosen N, Garg TK, Malaviarachchi PA, Moreno A, Dupont B, Hsu KC, Baxter-Lowe LA, Cottler-Fox M, Shaughnessy JD Jr, Barlogie B, van Rhee F. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol 2008; 143: 641-53.
- 17 Huenecke S, Zimmermann SY, Kloess S, Esser R, Brinkmann A, Tramsen L, Koenig M, Erben S, Seidl C, Tonn T, Eggert A, Schramm A, Bader P, Klingebiel T, Lehrnbecher T, Passweg JR, Soerensen J, Schwabe D, Koehl U. IL-2-driven regulation of NK cell receptors with regard to the distribution of CD16+ and CD16- subpopulations and in vivo influence after haploidentical NK cell infusion. J Immunother 2010; 33: 200-10.
- 18 Koehl U, Esser R, Zimmermann S, Tonn T, Kotchetkov R, Bartling T, Sörensen J, Gruttner HP, Bader P, Seifried E, Martin H, Lang P, Passweg JR, Klingebiel T, Schwabe D. Ex vivo expansion of highly purified NK cells for immunotherapy after haploidentical stem cell transplantation in children. Klin Padiatr 2005; 217: 345-50.
- 19 Passweg JR, Tichelli A, Meyer-Monard S, Heim D, Stern M, Kühne T, Favre G, Gratwohl A. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 2004; 18: 1835-88.
- 20 Yoon SR, Lee YS, Yang SH, Ahn KH, Lee JH, Lee JH, Kim DY, Kang YA, Jeon M, Seol M, Ryu SG, Chung JW, Choi I, Lee KH. Generation of donor natural killer cells from CD34(+) progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study. Bone Marrow Transplant 2010; 45: 1038-46.
- 21 Leung W, Iyengar R, Turner V, Lang P, Bader P, Conn P, Niethammer D, Handgretinger R. Determinants of antileu-kemia effects of allogeneic NK cells. J Immunol 2004; 172: 644-50.
- 22 Hsu KC, Keever-Taylor CA, Wilton A, Pinto C, Heller G, Arkun K, O'Reilly RJ, Horowitz MM, Dupont B. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 2005; 105: 4878-84.
- 23 Yu J, Venstrom JM, Liu XR, Pring J, Hasan RS, O'Reilly RJ, Hsu KC. Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood 2009; 113: 3875-84.
- 24 Meyer-Monard S, Passweg J, Siegler U, Kalberer C, Koehl U, Rovó A, Halter J, Stern M, Heim D, Alois Gratwohl JR, Tichelli A. Clinical-grade purification of natural killer cells in haploidentical hematopoietic stem cell transplantation. Transfusion 2009; 49: 362-71.
- 25 Iyengar R, Handgretinger R, Babarin-Dorner A, Leimig T, Otto M, Geiger TL, Holladay MS, Houston J, Leung W. Purification of human natural killer cells using a clinical-scale immunomagnetic method. Cytotherapy 2003; 5: 479-84.
- 26 Bethge WA, Haegele M, Faul C, Lang P, Schumm M, Bornhauser M, Handgretinger R, Kanz L. Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol 2006; 34: 1746-52.
- 27 Chen X, Hale GA, Barfield R, Benaim E, Leung WH, Knowles J, Horwitz EM, Woodard P, Kasow K, Yusuf U, Behm FG, Hayden RT, Shurtleff SA, Turner V, Srivastava DK, Handgretinger R. Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol 2006; 135: 524-32.
- 28 Symons HJ, Leffell MS, Rossiter ND, Zahurak M, Jones RJ, Fuchs EJ. Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2010; 16: 533-42.
- 29 Zhang Y, Wallace DL, de Lara CM, Ghattas H, Asquith B, Worth A, Griffin GE, Taylor GP, Tough DF, Beverley PC, Macallan DC. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 2007; 121: 258-65.
- 30 Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 2010; 115: 4293-301.
Citing Literature
