title: HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse.
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 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/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.
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy; Hematology Section, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy;
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Loredana
authors.initials: L
authors.lastname: Ruggeri
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Franca
authors.initials: F
authors.lastname: Falzetti
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Adelmo
authors.initials: A
authors.lastname: Terenzi
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Antonio
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Maria Speranza
authors.initials: MS
authors.lastname: Massei
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Lucia
authors.initials: L
authors.lastname: Amico
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Urbani
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Del Papa
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Tiziana
authors.initials: T
authors.lastname: Zei
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Iacucci Ostini
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Debora
authors.initials: D
authors.lastname: Cecchini
authors.affiliation: Blood Bank, Ospedale Santa Maria della Misericordia, Perugia, Italy;
authors.forename: Rita
authors.initials: R
authors.lastname: Tognellini
authors.affiliation: Weizmann Institute of Science, Immunology Department, Rehovot, Israel; and.
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Velardi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006648:Histocompatibility; D006801:Humans; D016219:Immunotherapy, Adoptive; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D006680:HLA Antigens