Purpose: Allogeneic haematopoietic stem-cell transplantation (HSCT) is a curative treatment for many haematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T-cells is a simple approach to rebuild immunity whilst limiting GvHD after haploidentical HSCT but the optimal T-cell dose and impact on immune reconstitution remain unknown. Experimental Design: We performed a multicentre Phase 1 trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution. Results: Nineteen high-risk acute leukemia or myelodysplasia patients were enrolled. Engraftment occurred in 18/19 patients (95%). Pre-aDLI, twelve patients (63%) had bacteremia, 9/17 at-risk patients (53%) reactivated CMV and one developed acute GvHD. Sixteen patients received aDLI at dose-levels 1 (103 T-cells/kg, n=4), 2 (104, n=8), and 3 (105, n=4). Post-aDLI, 5 patients developed clinically significant acute GvHD and 4/14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater and functional virus- and tumor-associated antigen-specific T-cells were detectable earlier in patients receiving dose-level 2 or 3 vs dose-level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T-cells. Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T-cells in vivo after CD34-selected myeloablative haploidentical HSCT.
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