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Adoptive Immunotherapy with Regulatory and Conventional T-cells in Haploidentical T-cell Depleted Transplantation Protects from GvHD and Exerts GvL Effect

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Haploidentical Transplantation

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Abstract

After conventional (“unmanipulated”) allogeneic hematopoietic cell transplantation, eradication of residual disease, i.e., the so-called graft-versus-leukemia (GvL) effect, depends on donor T-lymphocytes which recognize host histocompatibility antigens on leukemic cells. However, this transplant is far from optimal because it is associated with high incidence of relapse and risk of graft-versus-host disease (GvHD). Recent clinical trials suggest that adoptive immunotherapy with regulatory and conventional T-lymphocytes prevents GvHD while allowing a GvL effect in acute leukemia patients undergoing T-cell-depleted-haploidentical transplantation. We discuss the clinical relevance of this new immunotherapeutic strategy and the mechanisms underlying the separation of GvL effect from GvHD.

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References

  1. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300:1068–73.

    Article  CAS  PubMed  Google Scholar 

  2. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.

    CAS  PubMed  Google Scholar 

  3. Kloosterman TC, Martens AC, van Bekkum DW, et al. Graft-versus-leukemia in rat MHC-mismatched bone marrow transplantation is merely an allogeneic effect. Bone Marrow Transplant. 1995;15:583–90.

    CAS  PubMed  Google Scholar 

  4. Bortin MM, Truitt RL, Rimm AA, et al. Graft-versus-leukaemia reactivity induced by alloimmunisation without augmentation of graft-versus-host reactivity. Nature. 1979;281:490–1.

    Article  CAS  PubMed  Google Scholar 

  5. Reddy P, Maeda Y, Liu C, et al. A crucial role for antigen presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med. 2005;11:1244–9.

    Article  CAS  PubMed  Google Scholar 

  6. Rezvani K, Barrett AJ. Characterizing and optimizing immune responses to leukaemia antigens after allogeneic stem cell transplantation. Best Pract Res Clin Haematol. 2008;21:437–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gupta V, Talllman MS, He W, et al. Comparable survival after HLA-well matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavourable cytogenetics at diagnosis. Blood. 2010;116:1839–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Scaradavou A, Brunstein CG, Eapen M, et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. 2013;121:752–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Verneris MR, Brunstein CG, Barker JN, et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of two units. Blood. 2009;114:4293–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rocha V, Labopin M, Mohty M, et al. Outcomes after double unit unrelated cord blood transplantation (UCBT) compared with single UCBT in adults with acute leukemia in remission. A Eurocord and ALWP Collaboration study In abstract of ASH Annual Meeting. Blood. 2010;116:910a.

    Google Scholar 

  11. Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994;84:3948–55.

    CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. Ciceri F, Labopin M, Aversa F, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112:3574–81.

    Article  CAS  PubMed  Google Scholar 

  15. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 Transplantation. 2006;38:291–7.

    Article  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Arcese W, Picardi A, Santarone S, et al. Haploidentical, G-CSF-primed, unmanipulated bone marrow transplantation for patients with high-risk haematological malignancies: an update. Bone Marrow Transplant. 2015;50:S24–30.

    Article  CAS  PubMed  Google Scholar 

  24. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64.

    CAS  PubMed  Google Scholar 

  25. Hoffmann P, Ermann J, Edinger M, et al. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196:389–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nguyen VH, Zeiser R, daSilva DL, et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic stem cell transplantation. Blood. 2007;109:2649–56.

    Article  CAS  PubMed  Google Scholar 

  27. Nguyen VH, Shashidhar S, Chang DS, et al. The impact of regulatory T cells on T cell immunity following hematopoietic cell transplantation. Blood. 2008;111:945–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99:3493–9.

    Article  CAS  PubMed  Google Scholar 

  29. Cohen JL, Trenado A, Vasey D, et al. CD4(+) CD25(+) immunoregulatory T cells: new therapeutics for graft-versus host disease. J Exp Med. 2002;196:401–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Trenado A, Charlotte F, Fisson S, et al. Recipient type specific CD4+CD25+ regulatory T cells favour immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003;112:1688–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bolton HA, Zhu E, Terry AM, et al. Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease. J Clin Invest. 2015;125:3627–41.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gaidot A, Landau DA, Martin GH, et al. Immune reconstitution is preserved in hematopoietic stem cell transplantation coadministered with regulatory T cells for GVHD prevention. Blood. 2011;117:2975–83.

    Article  CAS  PubMed  Google Scholar 

  33. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  PubMed  Google Scholar 

  36. Brunstein CG, Miller JS, McKenna DH, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016;127:1044–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brunstein CG, Miller JS, Cao Q, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: Safety profile and detection kinetics. Blood. 2011;117:1061–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.

    CAS  PubMed  Google Scholar 

  39. Vence L, Palucka AK, Fay JW, et al. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2007;104:20884–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kelley TW, Parker CJ. CD4(+)CD25(+)FoxP3(+) regulatory T cells and haematological malignancies. Front Biosci. 2010;2:980–2.

    Article  Google Scholar 

  41. Ustun C, Miller JS, Munn DH, et al. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? Blood. 2011;118:5084–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ruggeri L, Di Ianni M, Falzetti F. Preventing GvHD and high-risk acute leukemia relapse by Treg and Tcon adoptive immunotherapy in HLA haploidentical transplantation: an update on the clinical trial and insights from murine studies. In Abstract EBMT, Istanbul; 2015.

    Google Scholar 

  43. Booth NJ, McQuaid AJ, Sobande T, et al. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol. 2010;184:4317–26.

    Article  CAS  PubMed  Google Scholar 

  44. Fujisaki J, Wu J, Carlson AL, et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474:216–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wong JYC, Liu A, Schultheiss T, et al. Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation. Biol Blood Marrow Transplant. 2006;12:306–15.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy

    Massimo F. Martelli, Mauro Di Ianni & Loredana Ruggeri

  2. Department of Medicine and Aging Sciences, University of Chieti-Pescara, Pescara, Italy

    Mauro Di Ianni

Authors
  1. Massimo F. Martelli
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  2. Mauro Di Ianni
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  3. Loredana Ruggeri
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Correspondence to Loredana Ruggeri .

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Editors and Affiliations

  1. Department of Stem Cell Transplantation, MD Anderson Cancer Center, Houston, Texas, USA

    Stefan O. Ciurea

  2. Department of General Pediatrics and Hematology/Oncology, University Children’s Hospital, Tübingen, Baden-Württemberg, Germany

    Rupert Handgretinger

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Martelli, M.F., Di Ianni, M., Ruggeri, L. (2018). Adoptive Immunotherapy with Regulatory and Conventional T-cells in Haploidentical T-cell Depleted Transplantation Protects from GvHD and Exerts GvL Effect. In: Ciurea, S., Handgretinger, R. (eds) Haploidentical Transplantation. Advances and Controversies in Hematopoietic Transplantation and Cell Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-54310-9_4

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  • DOI: https://doi.org/10.1007/978-3-319-54310-9_4

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-54309-3

  • Online ISBN: 978-3-319-54310-9

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