BACKGROUND. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively.
METHODS. In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution.
RESULTS. All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell–replete grafts. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years.
CONCLUSION. Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory.
(A and B) pp65NLV-specific T cells were detected by MHCI-tetramer staining of peripheral blood samples from HLA-A*0201+ CMV+ donors and in their respective recipients after HCT. (A) The time course of expansion of pp65NLV tetramer+ cells (right y axis, solid lines, absolute number of CD8+ pp65NLV+ T cells/μl in recipient peripheral blood at days 28, 56, and 80 after HCT) in relation to blood CMV copy number (left y axis, dashed lines) for 3 representative patients. Data shown at time 0 (black triangles) are from donor blood (D) (CD8+ pp65NLV+ T cells/μl). The 3 patients shown in A are representative of a total of 7 patients; the data for all 7 are shown in B. (B) The percentage of pp65NLV tetramer+ cells among CD8+ T cells and absolute numbers of pp65NLV tetramer+ CD8+ T cells in peripheral blood. (C) Expression of CD27 and CD28 on pp65NLV tetramer+ cells (blue overlay) and total CD8+ cells (red underlay) from 3 representative patients at day 56 and IL-2 and IFN-γ production on day 56 in response to pp65 peptide stimulation (gated on CD8+ cells).