Blood Journal
Leading the way in experimental and clinical research in hematology

HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse

  1. Massimo F. Martelli1,
  2. Mauro Di Ianni1,2,
  3. Loredana Ruggeri1,
  4. Franca Falzetti1,
  5. Alessandra Carotti1,
  6. Adelmo Terenzi1,
  7. Antonio Pierini1,
  8. Maria Speranza Massei1,
  9. Lucia Amico1,
  10. Elena Urbani1,
  11. Beatrice Del Papa1,
  12. Tiziana Zei1,
  13. Roberta Iacucci Ostini1,
  14. Debora Cecchini1,
  15. Rita Tognellini3,
  16. Yair Reisner4,
  17. Franco Aversa5,
  18. Brunangelo Falini1, and
  19. Andrea Velardi1
  1. 1Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
  2. 2Hematology Section, Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy;
  3. 3Blood Bank, Ospedale Santa Maria della Misericordia, Perugia, Italy;
  4. 4Weizmann Institute of Science, Immunology Department, Rehovot, Israel; and
  5. 5Hematology and Bone Marrow Transplant Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy

Key Points

  • Haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents high-risk acute leukemia relapse.

  • The GVL effect is separated from GVHD even across major HLA barriers.

Abstract

Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation–based regimen. Grafts included CD34+ cells (mean 9.7 × 106/kg), Tregs (mean 2.5 × 106/kg), and Tcons (mean 1.1 × 106/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow.

  • Submitted March 26, 2014.
  • Accepted June 4, 2014.
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