Haploidentical Transplants and NK Cell Alloreactivity

Chapter
Part of the Advances and Controversies in Hematopoietic Transplantation and Cell Therapy book series (ACHTCT)

Abstract

Allogeneic hematopoietic cell transplantation is the most powerful form of immunotherapy for neoplastic hematological diseases as well as selected nonmalignant hematological disorders. Matching donor and recipient at HLA level is crucial for optimal transplant outcomes with acceptable non-relapse mortality. However, only 25% of individuals have an HLA-identical sibling who could serve as donor. Alternative hematopoietic graft sources are HLA-matched unrelated volunteers, unrelated umbilical cord blood units, and HLA haplotype-mismatched (“haploidentical”) family members which are, however, associated with up to 40% NRM due to diverse combinations of graft failure, GvHD, hepatic sinusoidal obstruction syndrome, and infections. Donor-versus-recipient NK cell alloreactivity is now established as a key therapeutic element in T-cell-depleted haploidentical hematopoietic transplantation for acute myeloid leukemia. Under T-cell-replete protocols, the benefits of NK cell alloreactivity might be expected to be antagonized/obscured as was reported in unrelated donor and cord blood transplantation. The only exception so far documented is the haploidentical hematopoietic cell transplant trial with Treg/Tcon add-backs that, however, do not use any posttransplant pharmacologic immunosuppressive GvHD prophylaxis. In this chapter we will discuss the various methods used in studies to augment NK cell alloreactivity in haploidentical transplantation.

Keywords

Haploidentical transplant NK cells GvHD GvT-cell depletion HvKIR Alloreactivity 

References

  1. 1.
    Martelli MF, Di Ianni M, Ruggeri L, et al. “Designed” grafts for HLA-haploidentical stem cell transplantation. Blood. 2014;123:967–73.CrossRefGoogle Scholar
  2. 2.
    Huang X-J, Liu D-H, Liu K-Y, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006;38:291–7.CrossRefGoogle Scholar
  3. 3.
    Wang Y, Liu QF, LP X, et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015;125:3956–62.CrossRefGoogle Scholar
  4. 4.
    Di Bartolomeo P, Santarone S, De Angelis G, et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood. 2013;121:849–57.CrossRefGoogle Scholar
  5. 5.
    Luznik L, O’Donnell P, Symons H, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.CrossRefGoogle Scholar
  6. 6.
    Ciurea SO, Zhang M-J, Bacigalupo A, et al. Haploidentical transplant with post-transplant cyclophosphamide versus matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126:1033–40.CrossRefGoogle Scholar
  7. 7.
    Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998;339:1186–93.CrossRefGoogle Scholar
  8. 8.
    Aversa F, Terenzi A, Tabilio A, et al. 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.CrossRefGoogle Scholar
  9. 9.
    Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94:333–9.PubMedGoogle Scholar
  10. 10.
    Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100.CrossRefGoogle Scholar
  11. 11.
    Ruggeri L, Mancusi A, Capanni M, et al. 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.CrossRefGoogle Scholar
  12. 12.
    Velardi A, Ruggeri L, Mancusi A, et al. Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. Curr Opin Immunol. 2009;21:525–30.CrossRefGoogle Scholar
  13. 13.
    Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9.CrossRefGoogle Scholar
  14. 14.
    Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201–14.CrossRefGoogle Scholar
  15. 15.
    Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell. 2010;142:847–56.CrossRefGoogle Scholar
  16. 16.
    Joncker NT, Raulet DH. Regulation of NK cell responsiveness to achieve self- tolerance and maximal responses to diseased target cells. Immunol Rev. 2008;224:85–97.CrossRefGoogle Scholar
  17. 17.
    Elliott JM, Yokoyama WM. Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol. 2011;32:364–72.CrossRefGoogle Scholar
  18. 18.
    Fernandez NC, Treiner E, Vance RE, et al. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood. 2005;105:4416–23.CrossRefGoogle Scholar
  19. 19.
    Anfossi N, Andre P, Guia S, et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;25:331–42.CrossRefGoogle Scholar
  20. 20.
    Haas P, Loiseau P, Tamouza R, et al. NK-cell education is shaped by donor HLA genotype after unrelated allogeneic hematopoietic stem cell transplantation. Blood. 2011;117:1021–9.CrossRefGoogle Scholar
  21. 21.
    Mancusi A, Ruggeri L, Urbani E, et al. Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRs reduces non-relapse mortality. Blood. 2015;125:3173–82.CrossRefGoogle Scholar
  22. 22.
    Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol. 2004;172:644–50.CrossRefGoogle Scholar
  23. 23.
    Leung W, Iyengar R, Triplett B, et al. Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. J Immunol. 2005;174:6540–5.CrossRefGoogle Scholar
  24. 24.
    Hsu KC, Gooley T, Malkki M, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2006;12:828–36.CrossRefGoogle Scholar
  25. 25.
    Hsu KC, Keever-Taylor CA, Wilton A, et al. 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.CrossRefGoogle Scholar
  26. 26.
    Hsu KC, Pinto-Agnello C, Gooley T, et al. Hematopoietic stem cell transplantation: killer immunoglobulin-like receptor component. Tissue Antigens. 2007;69:42–5.CrossRefGoogle Scholar
  27. 27.
    Miller JS, Cooley S, Parham P, et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood. 2007;109:5058–61.CrossRefGoogle Scholar
  28. 28.
    Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory and activating killer Ig-like receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors. Bone Marrow Transplant. 2012;47:817–23.CrossRefGoogle Scholar
  29. 29.
    Kasamon YL, Luznik L, Leffell MS, et al. Significance of missing inhibitory KIR ligands in nonmyeloablative, HLA-haploidentical (haplo) BMT with post-transplantation high-dose cyclophosphamide (PT/Cy). ASH annual meeting abstracts. Blood. 2011;118:840.Google Scholar
  30. 30.
    AT B¨r, Schaffer M, Fauriat C, et al. NK cells expressing inhibitory KIR for nonself-ligands remain tolerant in HLA-matched sibling stem cell transplantation. Blood. 2010;115:2686–94.CrossRefGoogle Scholar
  31. 31.
    Pende D, Marcenaro S, Falco M, et al. Antileukemia 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;113:3119–29.CrossRefGoogle Scholar
  32. 32.
    Davies SM, Ruggeri L, DeFor T, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood. 2002;100:3825–7.CrossRefGoogle Scholar
  33. 33.
    Lowe EJ, Turner V, Handgretinger R, et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-nonidentical paediatric bone marrow transplantation. Br J Haematol. 2003;123:323–6.CrossRefGoogle Scholar
  34. 34.
    Bornhauser M, Schwerdtfeger R, Martin H, et al. Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood. 2004;103:2860–1.CrossRefGoogle Scholar
  35. 35.
    Farag SS, Bacigalupo A, Eapen M, et al. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the Center for International Blood and Marrow Transplant Research, the European Blood and Marrow Transplant Registry, and the Dutch registry. Biol Blood Marrow Transplant. 2006;12:876–84.CrossRefGoogle Scholar
  36. 36.
    Kröger N, Binder T, Zabelina T, et al. Low number of donor activating killer immunoglobulin-like receptors (KIR) genes but not KIR-ligand mismatch prevents relapse and improves disease-free survival in leukemia patients after in vivo T-cell depleted unrelated stem cell transplantation. Transplantation. 2006;82:1024–30.CrossRefGoogle Scholar
  37. 37.
    Yabe T, Matsuo K, Hirayasu K et al.; Japan Marrow Donor Program. Donor killer immunoglobulin-like receptor (KIR) genotype–patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantation. Biol Blood Marrow Transplant 2008;14:75–87.Google Scholar
  38. 38.
    Giebel S, Locatelli F, Lamparelli T, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood. 2003;102:814–9.CrossRefGoogle Scholar
  39. 39.
    Beelen DW, Ottinger HD, Ferencik S, et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood. 2005;105:2594–600.CrossRefGoogle Scholar
  40. 40.
    Elmaagacli AH, Ottinger H, Koldehoff M, et al. Reduced risk for molecular disease in patients with chronic myeloid leukemia after transplantation from a KIR-mismatched donor. Transplant. 2005;79:1741–7.CrossRefGoogle Scholar
  41. 41.
    Kröger N, Shaw B, Iacobelli S, et al. 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;129:631–43.CrossRefGoogle Scholar
  42. 42.
    Dawson MA, Spencer A. Successful use of haploidentical stem-cell transplantation with KIR mismatch as initial therapy for poor-risk myelodysplastic syndrome. J Clin Oncol. 2005;23:4473–4.CrossRefGoogle Scholar
  43. 43.
    Willemze R, Rodrigues CA, Labopin M, et al. KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia. 2009;23:492–500.CrossRefGoogle Scholar
  44. 44.
    Brunstein CG, Wagner JE, Weisdorf DJ, et al. Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity. Blood. 2009;113:5628–34.CrossRefGoogle Scholar
  45. 45.
    Ciceri F, Bonini C, Stanghellini MTL, et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a nonrandomised phase I–II study. Lancet Oncol. 2009;10:489–500.CrossRefGoogle Scholar
  46. 46.
    Vago L, Forno B, Sormani MP, et al. 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.CrossRefGoogle Scholar
  47. 47.
    Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8.CrossRefGoogle Scholar
  48. 48.
    Martelli MF, Di Ianni M, Ruggeri L, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124:638–44.CrossRefGoogle Scholar
  49. 49.
    Orleans-Lindsay JK, Barber LD, et al. Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function: implications for the adoptive immunotherapy of leukaemia. Clin Exp Immunol. 2001;126:403–11.CrossRefGoogle Scholar
  50. 50.
    Rood JJ, Eernisse JG, van Leeuwen A, et al. Leucocyte antibodies in sera of pregnant women. Nature. 1958;181:1735–6.CrossRefGoogle Scholar
  51. 51.
    Van Kampen CA, Versteeg-van der Voort Maarschalk MF, Langerak-Langerak J, et al. Pregnancy can induce long-persisting primed CTLs specific for inherited paternal HLA antigens. Hum Immunol. 2001;62:201–7.CrossRefGoogle Scholar
  52. 52.
    Verdijk RM, Kloosterman A, Pool J, et al. Pregnancy induces minor istocompatibility antigen-specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy. Blood. 2004;103:1961–4.CrossRefGoogle Scholar
  53. 53.
    Stern M, Ruggeri L, Mancusi A, et al. Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood. 2008;112:2990–5.CrossRefGoogle Scholar
  54. 54.
    Handgretinger R. Donor choice in haploidentical stem cell transplantation: fetal microchimerism is associated with better outcome in pediatric leukemia patients. Bone Marrow Transplant. 2015;50:1367–70.CrossRefGoogle Scholar
  55. 55.
    Wang Y, Chang YJ, LP X, et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood. 2014;124:843–50.CrossRefGoogle Scholar
  56. 56.
    Velardi A, Ziagkos D, van Biezen A, et al. Mother donors improve outcomes after HLA haploidentical hematopoietic transplantation: a retrospective study by the Cell Therapy and Immunobiology Working Party of the EBMT. Paper presented as a poster at EBMT 2016, Valencia, Spain; 2016.Google Scholar
  57. 57.
    Federmann B, Bornhauser M, Meisner C, et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study. Haematologica. 2012;97:1523–931.CrossRefGoogle Scholar
  58. 58.
    Handgretinger R, Lang P, Feuchtinger TF, et al. Transplantation of TcRab/CD19 depleted stem cells from haploidentical donors: robust engraftment and rapid immune reconstitution in children with high risk leukemia. ASH annual meeting abstracts 2011;118:1005.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Blood and Marrow Transplant ProgramUniversity of PerugiaPerugiaItaly

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