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A major complication of mismatched unmanipulated hematopoietic stem cell transplant (HSCT) is Graft-versus-Host Disease (GvHD), which results in significant morbidity and increased non-relapse mortality. Novel strategies to reduce GvHD and improve long-term tolerance between mismatched donor-host pairs include regulatory T cell therapy. We are investigating a new cell product named T-allo10 which contains suppressive anergic cells and is enriched in IL-10 producing regulatory type 1 T cells (Tr1). The main advantage of adoptive immunotherapy with Tr1 compared to other regulatory T cells is the host alloantigen specificity that is established in the donor Tr1 during in vitro culture in the presence of IL-10 and host tolerogenic dendritic cells. Here we report the preliminary results of our phase I trial (IND 17292) on the use of escalating doses of T-allo10 cells for patients aged 3-45 years affected by hematological malignancies. At present, we completed the first cohort of the phase I portion of the study (Table 1). The donors were class I mismatched for patient 1 and class II HLA-mismatched for patients 2 and 3, respectively. The GvHD prophylaxis consisted of Sirolimus and Mycophenolate and was serotherapy and Calcineurin inhibitory-free. Patients received 1 × 106 T-allo10 cells/Kg on Day-1. No adverse events were observed after the T-allo10 cell infusion. All 3 patients met the safety criteria and are alive and disease-free at 2 years, 15 months and 2 months post-HSCT, respectively. Tr1, phenotypically defined as CD4+CD45RA−CD49b+LAG3+ were detectable in the peripheral blood shortly after the infusion at 21% and 26% in patient 2 and 3, respectively. At day 28 post-HSCT, Tr1 represented 12% of circulating memory CD4+ T cells in patient 1, 3% in patient 2 and 2% in patient 3. TCR sequencing of T-allo10 cells prior and after infusion showed a restricted clonotype diversity with persistence of certain clonotypes in vivo, demonstrating Tr1 cell recirculation and survival. These data show that the T-allo10 cell infusion is safe and well tolerated and demonstrate that T-allo10 cells are detectable in the recipients after the infusion and traceable by TCR clonotype analysis. [ABSTRACT FROM AUTHOR]