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Long-term follow-up of treg-based immunotherapy in HLA-haploidentical stem cell transplantation

      The present study evaluated the impact of an infusion of donor CD4/CD25+ Tregs, followed by an inoculum of donor mature T cells (Tcons) and positively immunoselected CD34+ cells in the setting of haploidentical stem cell transplantation. We selected T regulatory cells (Tregs) from standard leukapheresis using double-negative selection (anti-CD8 and anti-CD19) followed by positive selection (anti-CD25) and 72 procedures were performed. A median of 263 × 106 cells were recovered with a mean of CD4+/CD25+ cells of 94.5 ± 2.4% (36.5 ± 18.6% CD4+/CD25+hi). FoxP3+ cells were equal to 79.8% ± 22.2. CD127+ cells were 12.5% ± 8.2. The inhibition assay showed an inhibition rate of 67 ± 22. Twenty-eight patients (22 AML; 5 ALL; 1 NHL) after a conditioning regimen consisting in TBI, thiotepa, fludarabine and cyclophosphamide, received immunoselected Tregs (2 to 4 × 106/kg bw) and 4 days later CD34+ cells (median 8.2 × 106/kg bw) together with Tcons (0.5 to 2 × 106/kg bw). No GvHD prophylaxis was administered. 26/28 patients engrafted. Only 2 patients developed ≥ grade II GvHD. No chronic GvHD was observed. CD4+ and CD8+ peripheral blood counts reached 200/μL on days 70 and 51 respectively. We observed a rapid development of a wide T-cell repertoire and high frequencies of specific CD4+ and CD8+ clones for opportunistic pathogens. Treg immunotherapy did not compromise post-transplant generation of donor-vs-recipient alloreactive natural killer (NK) cell repertoires which was faster than controls and with an enhanced alloreactivity against KIR-ligand mismatched targets. The cumulative incidence of relapse was 0.02 as only 1 high risk patients have relapsed to date. At a mean follow-up of 3.51 years (range 3.2–4.1), 11 patients are alive and leukaemia-free. In conclusion, in the setting of haploidentical transplantation infusion of Tregs makes administration of a high dose of T cells feasible for the first time. This strategy provides a long-term protection from GvHD, a robust immune reconstitution and preserves the GvL effect.
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