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Haploidentical HSCT: a 15-year experience at San Raffaele

Bone Marrow Transplantation volume 50, pages S67–S71 (2015)Cite this article

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Abstract

Hematopoietic SCT (HSCT) from HLA haploidentical family donors is a promising therapy for high-risk hematological malignancies. In the past 15 years at San Raffaele Scientific Institute, we investigated several transplant platforms and post transplant cellular-based interventions. We showed that T cell-depleted haploidentical transplantation followed by the infusion of genetically modified donor T cells (TK007 study, Eudract-2005-003587-34) promotes fast and wide immune reconstitution and GvHD control. This approach is currently tested in a phase III multicenter randomized trial (TK008 study, NCT00914628). We targeted patients with advanced leukemia with a sirolimus-based, calcineurin inhibitor-free prophylaxis of GvHD to allow the safe infusion of unmanipulated PBSCs from haploidentical family donors (TrRaMM study, Eudract 2007-5477-54). Results of these approaches are summarized and discussed.

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References

  1. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F 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: 1186–1193.

    Article  CAS  Google Scholar 

  2. Aversa F, Terenzi A, Carotti A, Felicini R, Jacucci R, Zei T et al. Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia. J Clin Oncol 1999; 17: 1545–1550.

    Article  CAS  Google Scholar 

  3. Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P et al. A survey of fully-haploidentical hematopoietic stem cells transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients transplanted in remission. Blood 2008; 112: 3574–3581.

    Article  CAS  Google Scholar 

  4. Cieri N, Mastaglio S, Oliveira G, Casucci M, Bondanza A, Bonini C . Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation. Immunol Rev 2014; 257: 165–180.

    Article  CAS  Google Scholar 

  5. Andre-Schmutz I, Le Deist F, Hacein-Bey-Abina S, Vitetta E, Schindler J, Chedeville G et al. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet 2002; 360: 130–137.

    Article  Google Scholar 

  6. Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 2006; 108: 1797–1808.

    Article  CAS  Google Scholar 

  7. Hartwig UF, Nonn M, Khan S, Meyer RG, Huber C, Herr W . Depletion of alloreactive T cells via CD69: implications on antiviral, antileukemic and immunoregulatory T lymphocytes. Bone Marrow Transplant 2006; 37: 297–305.

    Article  CAS  Google Scholar 

  8. Hartwig UF, Nonn M, Khan S, Link I, Huber C, Herr W . Depletion of alloreactive donor T lymphocytes by CD95-mediated activation-induced cell death retains antileukemic, antiviral, and immunoregulatory T cell immunity. Biol Blood Marrow Transplant 2008; 14: 99–109.

    Article  CAS  Google Scholar 

  9. Wehler TC, Nonn M, Brandt B, Britten CM, Grone M, Todorova M et al. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007; 109: 365–373.

    Article  CAS  Google Scholar 

  10. McIver ZA, Melenhorst JJ, Grim A, Naguib N, Weber G, Fellowes V et al. Immune reconstitution in recipients of photodepleted HLA-identical sibling donor stem cell transplantations: T cell subset frequencies predict outcome. Biol Blood Marrow Transplant 2011; 17: 1846–1854.

    Article  CAS  Google Scholar 

  11. Foster AE, Marangolo M, Sartor MM, Alexander SI, Hu M, Bradstock KF et al. Human CD62L- memory T cells are less responsive to alloantigen stimulation than CD62L+ naive T cells: potential for adoptive immunotherapy and allodepletion. Blood 2004; 104: 2403–2409.

    Article  CAS  Google Scholar 

  12. Alyea EP, Canning C, Neuberg D, Daley H, Houde H, Giralt S et al. CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant 2004; 34: 123–128.

    Article  CAS  Google Scholar 

  13. Ho VT, Kim HT, Li S, Hochberg EP, Cutler C, Lee SJ et al. Partial CD8+ T-cell depletion of allogeneic peripheral blood stem cell transplantation is insufficient to prevent graft-versus-host disease. Bone Marrow Transplant 2004; 34: 987–994.

    Article  CAS  Google Scholar 

  14. Dodero A, Carniti C, Raganato A, Vendramin A, Farina L, Spina F et al. Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery. Blood 2009; 113: 4771–4779.

    Article  CAS  Google Scholar 

  15. Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R et al. HLA-haploidentical stem cell transplantation after removal of alphabeta+ T and B cells in children with nonmalignant disorders. Blood 2014; 124: 822–826.

    Article  CAS  Google Scholar 

  16. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft versus leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  Google Scholar 

  17. Appelbaum FR . Haematopoietic cell transplantation as immunotherapy. Nature 2001; 411: 385–389.

    Article  CAS  Google Scholar 

  18. Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009; 361: 478–488.

    Article  CAS  Google Scholar 

  19. Peccatori J, Forcina A, Clerici D, Crocchiolo R, Vago L, Stanghellini MT et al. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors. Leukemia 2015; 129: 396–405.

    Article  Google Scholar 

  20. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M et al. T Lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 1995; 270: 475–480.

    Article  CAS  Google Scholar 

  21. Bordignon C, Notarangelo LD, Nobili N, Ferrari G, Casorati G, Panina P et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science 1995; 270: 470–475.

    Article  CAS  Google Scholar 

  22. Bonini C, Grez M, Traversari C, Ciceri F, Marktel S, Ferrari G et al. Safety of retroviral gene marking with a truncated NGF receptor. Nat Med 2003; 9: 367–369.

    Article  CAS  Google Scholar 

  23. Ciceri F, Bonini C, Marktel S, Zappone E, Servida P, Bernardi M et al. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood 2007; 109: 4698–4707.

    Article  CAS  Google Scholar 

  24. Vago L, Oliveira G, Bondanza A, Noviello M, Soldati C, Ghio D et al. T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation. Blood 2012; 120: 1820–1830.

    Article  CAS  Google Scholar 

  25. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  Google Scholar 

  26. Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, Deconinck E et al. Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 2001; 97: 63–72.

    Article  CAS  Google Scholar 

  27. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol 2009; 10: 489–500.

    Article  Google Scholar 

  28. Fehse B, Ayuk FA, Kroger N, Fang L, Kuhlcke K, Heinzelmann M et al. Evidence for increased risk of secondary graft failure after in vivo depletion of suicide gene-modified T lymphocytes transplanted in conjunction with CD34+-enriched blood stem cells. Blood 2004; 104: 3408–3409.

    Article  CAS  Google Scholar 

  29. Onodera M . Gene and cell therapy for relapsed leukemia after allo-stem cell transplantation. Front Biosci 2008; 13: 3408–3414.

    Article  CAS  Google Scholar 

  30. Burt RK, Drobyski WR, Seregina T, Traynor A, Oyama Y, Keever-Taylor C et al. Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions. Exp Hematol 2003; 31: 903–910.

    Article  CAS  Google Scholar 

  31. Oelke M, Maus MV, Didiano D, June CH, Mackensen A, Schneck JP . Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nat Med 2003; 9: 619–624.

    Article  CAS  Google Scholar 

  32. Borchers S, Provasi E, Silvani A, Radrizzani M, Benati C, Dammann E et al. Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation. Hum Gene Ther 22: 829–841.

    Article  CAS  Google Scholar 

  33. Recchia A, Bonini C, Magnani Z, Urbinati F, Sartori D, Muraro S et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci USA 2006; 103: 1457–1462.

    Article  CAS  Google Scholar 

  34. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S 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: 3447–3454.

    Article  Google Scholar 

  35. Federmann B, Bornhauser M, Meisner C, Kordelas L, Beelen DW, Stuhler G et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study. Haematologica 2012; 97: 1523–1531.

    Article  CAS  Google Scholar 

  36. Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P 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: 3574–3581.

    Article  CAS  Google Scholar 

  37. Eapen M, Klein JP, Sanz GF, Spellman S, Ruggeri A, Anasetti C et al. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 2011; 12: 1214–1221.

    Article  CAS  Google Scholar 

  38. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W et al. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15: 257–265.

    Article  CAS  Google Scholar 

  39. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.

    Article  CAS  Google Scholar 

  40. Di Bartolomeo P, Santarone S, De Angelis G, Picardi A, Cudillo L, Cerretti R et al. Haploidentical, unmanipulated, G-CSF primed bone marrow transplantation for patients with high-risk hematological malignancies. Blood 2012; 121: 849–857.

    Article  Google Scholar 

  41. Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant 2012; 19: 117–122.

    Article  Google Scholar 

  42. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG . Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006; 177: 8338–8347.

    Article  CAS  Google Scholar 

  43. Sakaguchi S . Regulatory T cells: history and perspective. Methods Mol Biol 2011; 707: 3–17.

    Article  CAS  Google Scholar 

  44. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J 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: 1061–1070.

    Article  CAS  Google Scholar 

  45. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011; 117: 3921–3928.

    Article  CAS  Google Scholar 

  46. Teachey DT, Grupp SA, Brown VI . Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol 2009; 145: 569–580.

    Article  CAS  Google Scholar 

  47. Bacchetta R, Lucarelli B, Sartirana C, Gregori S, Lupo Stanghellini MT, Miqueu P et al. Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol 2014; 5: 16.

    Article  Google Scholar 

  48. Todisco E, Ciceri F, Oldani E, Boschini C, Mico C, Vanlint MT et al. The CIBMTR score predicts survival of AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: a retrospective analysis of the Gruppo Italiano Trapianto Di Midollo Osseo. Leukemia 2013; 27: 2086–2091.

    Article  CAS  Google Scholar 

  49. Cieri N, Greco R, Morelli M, Giglio F, Assanelli A, Forcina A et al Post-Transplant Cyclophosphamide Haplo-HSCT Revised: Peripheral Blood Stem Cell Graft and Sirolimus To Enhance Immune Reconstitution and Graft Versus Leukemia Effect In Patients With Active Leukemia. 122; Meeting Abstract: 2118 2013.

  50. Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ, Reik A et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat Med 2012; 18: 807–815.

    Article  CAS  Google Scholar 

  51. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood 2013; 122: 3461–3472.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge MolMed S.p.A., the Italian Ministry of Health, the Italian Ministry of University and Research and the Associazione Italiana Ricerca sul Cancro (AIRC), the EU commission (SUPERSIST).

Author information

Author notes

  1. E Zappone

    Present address: Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.,

Authors and Affiliations

  1. Experimental Hematology Unit, San Raffaele Scientific Institute, Milan, Italy

    C Bonini, A Bondanza, N Cieri & G Oliveira

  2. Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy

    J Peccatori, M T L Stanghellini, L Vago, R Greco, M Bernardi, C Corti, E Zappone & F Ciceri

  3. MolMed SpA, Milan, Italy

    C Traversari & C Bordignon

  4. ’Vita-Salute’ San Raffaele University, Milan, Italy

    C Bordignon

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  1. C Bonini
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  2. J Peccatori
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  3. M T L Stanghellini
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Corresponding author

Correspondence to F Ciceri.

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Competing interests

Prof. Claudio Bordignon and Dr Catia Traversari are employees of MolMed S.p.A., Milano, Italy. Prof. Bordignon also owns stock/equity in MolMed S.p.A. Chiara Bonini receives a research grant from MolMed s.p.a and has been a consultant of MolMed s.p.a. Attilio Bondanza has received grant support from Italian Association for Cancer Research and holds a patent ‘Use of common y-chain cytokines for the genetic modification of memory T lymphocytes’ EP1946080, US13240,009.

Additional information

This article was published as part of a supplement, supported by WIS-CSP Foundation, in collaboration with Gilead, Milteny Biotec, Gamida cell, Adienne Pharma and Biotech, Medac hematology, Kiadis Pharma, Almog Diagnostic.

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Bonini, C., Peccatori, J., Stanghellini, M. et al. Haploidentical HSCT: a 15-year experience at San Raffaele. Bone Marrow Transplant 50 (Suppl 2), S67–S71 (2015). https://doi.org/10.1038/bmt.2015.99

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