Single Infusion of Donor Mononuclear Early Apoptotic Cells as Prophylaxis for Graft-versus-Host Disease in Myeloablative HLA-Matched Allogeneic Bone Marrow Transplantation: A Phase I/IIa Clinical Trial

Abstract

Because of its potent immunomodulatory effect, an infusion of donor mononuclear early apoptotic cells (ApoCell) was tested in addition to cyclosporine and methotrexate as prophylaxis for acute graft-versus-host disease (GVHD) after HLA-matched myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor. In a phase I/IIa clinical trial, we treated 13 patients (median age, 37 years; range, 20 to 59 years) with hematologic malignancies: 7 patients with acute lymphoblastic leukemia, 5 patients with acute myeloid leukemia, and 1 patient with chronic myeloid leukemia, who received conventional myeloablative conditioning, with 35, 70, 140, or 210 × 10(6) cell/kg of donor ApoCell, on day -1 of transplantation. Engraftment was successful in all patients with median time to neutrophil recovery of 13 days (range, 11 to 19), and platelet recovery of 15 days (range, 11 to 59). Serious adverse effects were reported on 10 occasions in the trial, all of which were considered unrelated (n = 7) or unlikely to be related (n = 3) to ApoCell infusion. The nonrelapse mortality at day 100 and 180 after transplantation was 7.7% and the overall survival at 100 and 180 days after transplantation was 92% and 85%, respectively. All ApoCell preparations showed an in vitro significant tolerogenic effect upon interaction with dendritic cells. The overall incidence of acute grades II to IV GVHD was 23%, whereas among those receiving the 2 higher doses (n = 6), the rate was 0%. These results suggest that a single infusion of donor ApoCell in HLA-matched allogeneic HSCT is a safe and potentially effective prophylaxis for acute GVHD occurring after myeloablative conditioning. No dose limiting toxicity was observed. (Clinicaltrials.gov no. NCT00524784).

Prospects of Apoptotic Cell-Based Therapies for Transplantation and Inflammatory Diseases

“…A Phase I/IIa clinical trial has been performed in 13 patients without specific future science group Review Saas, Kaminski & Perruche toxicities and a good early outcome has been observed [127]. This confirms the feasibility of such cell-based therapy approaches in humans.…”

“…In experimental models (Table 3), infusion of apoptotic cells at time of transplantation induces TGF-b and increases Tregs that prevent GvHD occurrence [14,117,120]. Recently, a Phase I/IIa clinical study has been registered [201] and encouraging data have been presented recently in two meetings [126,127]. In this study, iv.…”

“…Comparison with historical data concerning acute GvHD occurrence in the same transplantation center or from the literature seems to show a reduction of high grade acute GvHD (grade >II). Interestingly, no severe GvHD was observed in the three patients receiving the highest apoptotic cell number [127]. This clinical study opens the way to apoptotic cell-based therapies in other clinical settings, which have already been assessed in experimental models (Table 3).…”

Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD

“…Graft-versus-host disease (GVHD) is one of the major complications after allogeneic HSCT [1][2][3]. The standard GVHD prophylaxis regimen is a combination of methotrexate (MTX) and a calcineurin inhibitor, such as cyclosporine A (CSA) or tacrolimus (TAC) [4][5][6].…”

Cellular therapy of the host to prevent GVHD

“…The resulting incidence of grade II to IV GVHD was 23% (with 0% for the 2 highest cell doses) and nonrelapse mortality was 8% at day 100. 9 Incubation of host DCs with these apoptotic cells also significantly decreased the cell surface expression of the activation markers HLA-DR and CD86. Future clinical trials of cellular therapy with apoptotic cells (potentially of either donor or host origin) to prevent GVHD will therefore be of great interest.…”