Interleukin-10 Anergized Donor T Cell Infusion Improves Immune Reconstitution without Severe Graft-Versus-Host-Disease After Haploidentical Hematopoietic Stem Cell Transplantation

• Published in: Blood 2009-11, Vol.114 (22), p.45-45
• Main Authors: Bacchetta, Rosa, Sartirana, Claudia, Lucarelli, Barbarella, Miqueu, Patrick, Stanghellini, Maria Teresa Lupo, Greco, Raffaella, Velardi, Andrea, Aversa, Franco, Martelli, Massimo F, Gregori, Silvia, Zappone, Elisabetta, Fleischhauer, Katharina, Bernardi, Massimo, Peccatori, Jacopo, Ciceri, Fabio, Roncarolo, Maria Grazia
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V114.22.45.45

Abstract 45 Background: Adoptive transfer of regulatory T cells is a potentially attractive alternative to conventional immunosuppressive therapy in allogeneic hematopoietic stem cell transplantation (HSCT) (Roncarolo MG., Nat Rev Immunol 2007). Among CD4+ T cells, the subset known as Type 1 regulatory T (Tr1) cells are induced in an antigen specific manner by interleukin-10 (IL-10) and suppress via production of high levels of IL-10 (Groux H., Nature 1997). The aim of this phase I/II study was to establish the safety and efficacy of a new cellular therapy with Tr1 cells in a non-randomized study. Patients and Methods: A cellular therapy protocol for the adoptive transfer of IL-10 induced alloantigen specific donor-derived Tr1 cells in patients transplanted with CD34+ selected cells from haploidentical donor, has been applied to patients with high risk hematopoietic malignancies (www.risetfp6.org). Donor T cells, anergized ex vivo toward host alloantigens, presented by monocytes (original protocol) or tolerogenic dendritic cells (modified protocol) as host antigen presenting cells, in the presence of IL-10, are infused post-transplant into the host (IL-10 DLI). The infusion is made in the absence of immunosuppression for graft-versus-host-disease (GVHD) prophylaxis, with the ultimate goal to provide immune reconstitution without severe GVHD. The infused donor T cells, at the dose of 105 CD3+ cells/kg or 3 × 105 CD3+ cells/kg, are anergic towards host-HLA antigens and contain precursors of host-specific Tr1 cells but, at the same time, comprise memory T cells able to respond to nominal and viral antigens. Results: Eighteen patients have been enrolled, sixteen received CD34+ selected cells from haploidentical donor after myeloablative conditioning. Twelve patients have been treated with IL-10 anergized cell therapy at day +30 post transplant, at the dose of 105 CD3+ cells/kg with the exception of two patients who received 3 × 105 CD3+ cells/kg. No severe immediate reactions post infusion were registered. Five patients died from infections by day +30 after Tregs cell infusion and two patients dropped out for graft rejection. Five patients achieved immune reconstitution at a median of 30,5 days (range 15–46 days) after IL-10 DLI, followed by progressive normalization of TCR repertoire, memory/naïve phenotype and T cell functions in vitro and in vivo. Acute GVHD grade III was observed in one patient who received 3 × 105 CD3+ cells/kg; GVHD grade II was observed