title: CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation.
abstract: Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T(reg)s) may reduce alloreactivity, the major component of the graft-versus-tumor effect. In the setting of donor lymphocyte infusion after hematopoietic stem cell transplantation, we postulated that T(reg) depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of T(reg)-depleted donor lymphocyte infusion was studied in 17 adult patients with malignancy relapse after hematopoietic stem cell transplantation. All but one had previously failed to respond to at least one standard donor lymphocyte infusion, and none had experienced graft-versus-host disease. Two of the 17 patients developed graft-versus-host disease after their first T(reg)-depleted donor lymphocyte infusion and experienced a long-term remission of their malignancy. Four of the 15 patients who did not respond after a first T(reg)-depleted donor lymphocyte infusion received a second T(reg)-depleted donor lymphocyte infusion combined with lymphodepleting chemotherapy aimed to also eliminate recipient T(reg)s. All four developed acute-like graft-versus-host disease that was associated with a partial or complete and durable remission. In the whole cohort, graft-versus-host disease induction through T(reg) depletion was associated with improved survival. These results suggest that T(reg)-depleted donor lymphocyte infusion is a safe, feasible approach that induces graft-versus-host or graft-versus-tumor effects in alloreactivity-resistant patients. In patients not responding to this approach, the combination of chemotherapy-induced lymphodepletion of the recipient synergizes with the effect of T(reg)-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy.
authors.affiliation: Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil F-94010, France. sebastien.maury@hmn.aphp.fr
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maury
authors.forename: François M
authors.initials: FM
authors.lastname: Lemoine
authors.forename: Yosr
authors.initials: Y
authors.lastname: Hicheri
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.forename: Mustapha
authors.initials: M
authors.lastname: Cheraï
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Beaumont
authors.forename: Nabih
authors.initials: N
authors.lastname: Azar
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhedin
authors.forename: Anne
authors.initials: A
authors.lastname: Sirvent
authors.forename: Agnès
authors.initials: A
authors.lastname: Buzyn
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Rubio
authors.forename: Stéphane
authors.initials: S
authors.lastname: Vigouroux
authors.forename: Olivier
authors.initials: O
authors.lastname: Montagne
authors.forename: Dominique
authors.initials: D
authors.lastname: Bories
authors.forename: Françoise
authors.initials: F
authors.lastname: Roudot-Thoraval
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vernant
authors.forename: Catherine
authors.initials: C
authors.lastname: Cordonnier
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.forename: José L
authors.initials: JL
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D020350:Graft vs Tumor Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000379:methods*; D055815:Young Adult
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit