title: A phase I study of CD25/regulatory T-cell-depleted donor lymphocyte infusion for relapse after allogeneic stem cell transplantation.
abstract: Donor lymphocyte infusions are used to treat relapse after allogeneic hematopoietic stem cell transplantation, but responses are inadequate. In addition to effector cells, infusions contain CD25+regulatory T cells (Treg) that may suppress graft-versus-tumor responses. We undertook a phase I study of donor lymphocyte infusions depleted of CD25+T cells in patients with hematologic malignancies who had relapsed after transplantation. Twenty-one subjects received CD25/Treg-depleted infusions following removal of CD25+cells using antibody-conjugated magnetic beads. Sixteen subjects received prior cytoreductive therapy. Four were in complete remission at the time of infusion. Two dose levels were administered: 1×107(n=6) and 3×107CD3+cells/kg (n=15). A median 2.3 log-depletion of CD4+CD25+FOXP3+Treg was achieved. Seven subjects (33%) developed clinically significant graft-versus-host disease by 1 year, including one patient who died. At dose level 1, five subjects had progressive disease and one had stable disease. At dose level 2, nine subjects (60%) achieved or maintained responses (8 complete responses, 1 partial response), including seven with active disease at the time of infusion. A shorter period between relapse and infusion was associated with response at dose level 2 (P=0.016). The 1-year survival rate was 53% among patients treated with dose level 2. Four of eight subjects with acute myeloid leukemia remained in remission at 1 year. When compared to unmodified donor lymphocyte infusions in 14 contemporaneous patients meeting study eligibility, CD25/Treg depletion was associated with a better response rate and improved event-free survival. Circulating naïve and central memory CD4+T cells increased after CD25/Treg-depleted infusion, but no immunophenotypic signature for response was noted. CD25/Treg-depleted donor infusion appears feasible and capable of inducing graft-versus-tumor responses without excessive graft-versus-host disease. (ClinicalTrials.gov NCT#00675831).
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA sarah_nikiforow@dfci.harvard.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard School of Public Health, Boston, MA, USA.
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Daley
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Reynolds
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Kyle Thomas
authors.initials: KT
authors.lastname: Jones
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D020350:Graft vs Tumor Effect; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D008212:Lymphocyte Depletion / Q000379:methods; D017710:Lymphocyte Transfusion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit