Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells

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.

Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance

“…In 2014, Bacchetta et al reported a small proof-of-concept clinical trial, in which IL-10-anergized T cells (Tr1 cells) and hematopoietic stem cells were transferred into patients with hematologic malignancies. 63 Of the 12 patients involved, four showed recurrence and survived beyond day 100, three failed to achieve the desired immune reconstruction and were prone to infection, four reached the target immune reconstitution with long-term optimal performance status, and the remaining patient obtained immune reconstitution although ultimately died of infection. 63 Compared with the previous clinical data on the risk of such procedures at an advanced stage of the disease, the therapy appears effective, safe, and promising.…”

“…63 Of the 12 patients involved, four showed recurrence and survived beyond day 100, three failed to achieve the desired immune reconstruction and were prone to infection, four reached the target immune reconstitution with long-term optimal performance status, and the remaining patient obtained immune reconstitution although ultimately died of infection. 63 Compared with the previous clinical data on the risk of such procedures at an advanced stage of the disease, the therapy appears effective, safe, and promising. 64,65 A phase I/II clinical trial was launched to determine whether OVA-specific Tr1 cells are effective in the treatment of refractory Crohn's disease.…”

Proceedings: Immune Tolerance and Stem Cell Transplantation: A CIRM Mini-Symposium and Workshop Report

“…Dr. MariaGrazia Roncarolo discussed recent results from the ALT-TEN trial testing a human Treg subpopulation, named Tr1, for its ability to promote immune recovery without severe graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell (HSC) transplant in patients with hematologic malignancies. Several transplanted patients showed long-term disease remission and the presence of donor-derived T cells, antigen-specific anergy, and other signs of Treg activity, demonstrating the safety and feasibility of this approach and providing preliminary evidence of a tolerance signature [15]. Treg-based trials, using FOXP31 Tregs, have been proven to be safe and to reduce GVHD in patients receiving allogeneic major histocompatibility complex-mismatched HSCs [16].…”

T Cell Immunotherapy for Immune Reconstitution and GVHD Prevention After Allogeneic Hematopoietic Stem Cell Transplantation

“…In fact, donor T cells primed ex vivo with host APCs and IL-10 are anergic towards host-HLA antigens but contain host-specific Tr1 cells and memory T cells able to respond to pathogens [93]. The five patients treated with this approach showed improved immune reconstitution, and four of them are alive with complete disease remission at 7.2 years (range 6.4-8.3) after HSCT [94,95], thus providing the first proof-of-concept of feasibility and safety of Tr1 cellbased therapy and suggesting a clinical benefit of the use of Tr1 cells after HLA-haploidentical HSCT.…”