A phase I study of CD25/regulatory T-cell-depleted donor lymphocyte infusion for relapse after allogeneic stem cell transplantation

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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 (Tregs) that may suppress graft-versus-tumor responses. We undertook a Phase I study of donor lymphocyte infusion depleted of CD25+ T cells in hematologic malignancies relapsed after transplantation. Twenty-one subjects received CD25/Treg-depleted infusion following removal of CD25+ cells using antibody-conjugated magnetic beads. Sixteen subjects received prior cytoreductive therapy. Four were in complete remission at infusion. Two dose levels were administered: 1x107 (n=6) and 3x107 CD3+ cells/kg (n=15). Median 2.3 log-depletion of CD4+CD25+FOXP3+ Tregs was achieved. Seven subjects (33%) developed clinically significant graft-versus-host disease by one year, including one fatal case. At Dose Level 1, five subjects demonstrated progression; one had stable disease. At Dose Level 2, nine subjects (60%) achieved/maintained responses (8 complete, 1 partial response), including seven with active disease at infusion. Shorter time from relapse to infusion was associated with response at Dose Level 2 (p=0.016). One-year survival was 53% at Dose Level 2. Four of 8 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 better response rate and improved event-free survival. Circulating naive 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)

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