Abstract
T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vβ repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders.
Highlights
The long-term benefit and wide applicability of T-cell-depleted (TCD) haploidentical-HSC transplantation, have been limited by slow immune reconstitution and high relapse rate [1,2,3,4,5,6]
In a murine model of allogeneic hematopoietic stem cell transplantation (HSCT), transfer of IL-10-anergized T cells prevented graft-versus-host disease (GvHD) [28]. These findings provided the rationale for the clinical use of IL-10-anergized donor T cells (IL-10-DLI) to support immune reconstitution without severe GvHD after allo-HSCT
This study indicates the feasibility of cell therapy with IL-10-DLI to promote fast immune reconstitution and tolerance after haplo-HSCT
Summary
The long-term benefit and wide applicability of T-cell-depleted (TCD) haploidentical-HSC transplantation (haplo-HSCT), have been limited by slow immune reconstitution and high relapse rate [1,2,3,4,5,6]. Infusion of unmanipulated donor lymphocyte (DLI) to improve immune reconstitution and to prevent relapse led to high incidence of severe graft-versus-host disease (GvHD) [3, 7]. Freshly isolated or expanded CD4+CD25+ T regulatory (Treg) cells have been used as adjuvant therapy to suppress GvHD after allogeneic HSCT in patients with hematologic malignancies [13,14,15]. These Treg cell therapies are safe, tested in a small number of patients, but their efficacy is still controversial. Many open questions remain on the best source of Treg cells to be administered, the optimal cell dose, the survival and behavior of these cells once they are in the host environment, and their mechanism of action
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