Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors

Catharina Van Elssen, Gwendolyn van Gorkom, Christine Voorter, Peter von dem Borne, Ellen Meijer, Lotte Wieten, Gerard Bos, Catharina Van Elssen, Gwendolyn van Gorkom, Christine Voorter, Peter von dem Borne, Ellen Meijer, Lotte Wieten, Gerard Bos

Abstract

Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts.Clinical Trial Registry: NCT02519114.

Keywords: Multiple myeloma; NK cells; Stem cell transplantation.

Conflict of interest statement

G. Bos is C.E.O. CiMaas bv, Maastricht, The Netherlands. All other authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Clinical outcomes after HaploBMT. a Probability of progression-free survival. b Overall survival
Fig. 2
Fig. 2
Serum-free light-chain response after HaploBMT in one individual patient. Progression 30 days after transplantation and responsive thereafter without treatment
Fig. 3
Fig. 3
a–d Assessment of NK cell phenotype after stem cell transplantation. Mononuclear cells were isolated from peripheral blood (PBL) or bone marrow (BM). To analyze KIR expression in the donor, PBL were harvested before from the donor before transplantation. To determine NK reconstitution upon transplantation, PBL or BM cells were isolated from the patient at 30 (d30) or 60 (d60) days after transplantation. Isolated cells were stained and the percentage of CD3-CD56+ NK cells expressing KIR2DL1, KIR2DL2/3, KIR3DL1, or NKG2A was determined by flow cytometry. Patients and their donors are depicted as P1–P8 in the legend and every dot represents one data point of cells analyzed at day 30 (d30) or day 60 (d60) after transplantation

References

    1. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–650. doi: 10.1016/j.bbmt.2008.03.005.
    1. McCurdy SR, Kasamon YL, Kanakry CG, Bolanos-Meade J, Tsai HL, Showel MM, et al. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica. 2017;102(2):391–400. doi: 10.3324/haematol.2016.144139.
    1. Sahebi F, Garderet L, Kanate AS, Eikema DJ, Knelange NS, Alvelo OFD, Koc Y, Blaise D, Bashir Q, Moraleda JM, Dreger P, Sanchez JF, Ciurea S, Schouten H, Shah NN, Verbeek M, Rösler W, Diez-Martin JL, Schoenland S, D'Souza A, Kröger N, Hari P. Outcomes of haploidentical transplantation in patients with relapsed multiple myeloma: an EBMT/CIBMTR report. Biol Blood Marrow Transplant. 2019;25(2):335–342. doi: 10.1016/j.bbmt.2018.09.018.
    1. Castagna L, Mussetti A, Devillier R, Dominietto A, Marcatti M, Milone G, Maura F, de Philippis C, Bruno B, Furst S, Blaise D, Corradini P, Montefusco V. Haploidentical allogeneic hematopoietic cell transplantation for multiple myeloma using post-transplantation cyclophosphamide graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2017;23(9):1549–1554. doi: 10.1016/j.bbmt.2017.05.006.
    1. Chen Y, Lu J, Xu LP, Chen H, Zhang XH, Wang FR, Chen YH, Wang Y, Liu KY, Huang XJ. Safety and efficacy of haploidentical stem cell transplantation for multiple myeloma. Bone Marrow Transplant. 2018;53(4):507–510. doi: 10.1038/s41409-017-0069-1.
    1. 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 (New York, NY) 2002;295(5562):2097–2100. doi: 10.1126/science.1068440.
    1. Pende D, Marcenaro S, Falco M, Martini S, Bernardo ME, Montagna D, Romeo E, Cognet C, Martinetti M, Maccario R, Mingari MC, Vivier E, Moretta L, Locatelli F, Moretta A. Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood. 2009;113(13):3119–3129. doi: 10.1182/blood-2008-06-164103.
    1. Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G, Maccario R, Bonetti F, Wojnar J, Martinetti M, Frassoni F, Giorgiani G, Bacigalupo A, Holowiecki J. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood. 2003;102(3):814–819. doi: 10.1182/blood-2003-01-0091.
    1. Wanquet A, Bramanti S, Harbi S, Furst S, Legrand F, Faucher C, et al. Killer cell immunoglobulin-like receptor-ligand mismatch in donor versus recipient direction provides better graft-versus-tumor effect in patients with hematologic malignancies undergoing allogeneic T cell-replete haploidentical transplantation followed by post-transplant cyclophosphamide. Biol Blood Marrow Transplant. 2018;24(3):549–554. doi: 10.1016/j.bbmt.2017.11.042.
    1. Bastos-Oreiro M, Anguita J, Martinez-Laperche C, Fernandez L, Buces E, Navarro A, et al. Inhibitory killer cell immunoglobulin-like receptor (iKIR) mismatches improve survival after T-cell-repleted haploidentical transplantation. Eur J Haematol. 2016;96(5):483–491. doi: 10.1111/ejh.12616.
    1. Willem C, Makanga DR, Guillaume T, Maniangou B, Legrand N, Gagne K, Peterlin P, Garnier A, Béné MC, Cesbron A, le Bourgeois A, Chevallier P, Retière C. Impact of KIR/HLA incompatibilities on NK cell reconstitution and clinical outcome after T cell-replete haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide. J Immunol. 2019;202(7):2141–2152. doi: 10.4049/jimmunol.1801489.
    1. Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N, Toffalori C, Zito L, Lorentino F, Piemontese S, Morelli M, Giglio F, Assanelli A, Stanghellini MTL, Bonini C, Peccatori J, Ciceri F, Luznik L, Vago L. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood. 2018;131(2):247–262. doi: 10.1182/blood-2017-05-780668.
    1. Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ, Miller JS. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood. 2005;106(13):4370–4376. doi: 10.1182/blood-2005-04-1644.
    1. Osterborg A, Nilsson B, Bjorkholm M, Holm G, Mellstedt H. Natural killer cell activity in monoclonal gammopathies: relation to disease activity. Eur J Haematol. 1990;45(3):153–157. doi: 10.1111/j.1600-0609.1990.tb00443.x.
    1. Frohn C, Hoppner M, Schlenke P, Kirchner H, Koritke P, Luhm J. Anti-myeloma activity of natural killer lymphocytes. Br J Haematol. 2002;119(3):660–664. doi: 10.1046/j.1365-2141.2002.03879.x.
    1. El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 2007;67(18):8444–8449. doi: 10.1158/0008-5472.CAN-06-4230.
    1. Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, Groh V, Spies T, Pollio G, Cosman D, Catalano L, Tassone P, Rotoli B, Venuta S. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105(1):251–258. doi: 10.1182/blood-2004-04-1422.
    1. Campbell KS, Cohen AD, Pazina T. Mechanisms of NK cell activation and clinical activity of the therapeutic SLAMF7 antibody, elotuzumab in multiple myeloma. Front Immunol. 2018;9:2551. doi: 10.3389/fimmu.2018.02551.
    1. Giuliani M, Janji B, Berchem G. Activation of NK cells and disruption of PD-L1/PD-1 axis: two different ways for lenalidomide to block myeloma progression. Oncotarget. 2017;8(14):24031–24044. doi: 10.18632/oncotarget.15234.
    1. Sarkar S, Germeraad WT, Rouschop KM, Steeghs EM, van Gelder M, Bos GM, et al. Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells. PLoS One. 2013;8(5):e64835. doi: 10.1371/journal.pone.0064835.
    1. Sarkar S, Noort W, van Elssen C, Groen R, van Bloois L, van Gelder M, Schouten H, Tilanus M, Germeraad W, Wieten L, Martens A, Bos G. Alloreactive Natural Killer cells have anti-tumor capacity against disseminated human multiple myeloma in Rag2-/-γC-/-mice when combined with low dose cyclophosphamide and total body irradiation. HSAO J Clin Immunol Immunother. 2015;2:008.
    1. 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 Jr JD, 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(5):641–653. doi: 10.1111/j.1365-2141.2008.07340.x.
    1. Kroger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A, Nagler A, Binder T, Eiermann T, Madrigal A, Schwerdtfeger R, Kiehl M, Sayer HG, Beyer J, Bornhauser M, Ayuk F, Zander AR, Marks DI, the Clinical Trial Committee of the British Society of Blood and Marrow Transplantation and the German Cooperative Transplant Group Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol. 2005;129(5):631–643. doi: 10.1111/j.1365-2141.2005.05513.x.
    1. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Bladé J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–ee46. doi: 10.1016/S1470-2045(16)30206-6.
    1. Nagler A, Dholaria B, Labopin M, Savani BN, Angelucci E, Koc Y et al (2020) Bone marrow versus mobilized peripheral blood stem cell graft in T-cell-replete haploidentical transplantation in acute lymphoblastic leukemia. Leukemia 34:2766–2775
    1. Ruggeri A, Labopin M, Bacigalupo A, Gulbas Z, Koc Y, Blaise D, et al. Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide. Cancer. 2018;124(7):1428–1437. doi: 10.1002/cncr.31228.
    1. Ciurea SO, Schafer JR, Bassett R, Denman CJ, Cao K, Willis D, Rondon G, Chen J, Soebbing D, Kaur I, Gulbis A, Ahmed S, Rezvani K, Shpall EJ, Lee DA, Champlin RE. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood. 2017;130(16):1857–1868. doi: 10.1182/blood-2017-05-785659.
    1. van Hall T, Andre P, Horowitz A, Ruan DF, Borst L, Zerbib R, et al. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer. 2019;7(1):263. doi: 10.1186/s40425-019-0761-3.

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