CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation.
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.
Maury
Sébastien
S
Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil F-94010, France. sebastien.maury@hmn.aphp.fr
Lemoine
François M
FM
Hicheri
Yosr
Y
Rosenzwajg
Michelle
M
Badoual
Cécile
C
Cheraï
Mustapha
M
Beaumont
Jean-Louis
JL
Azar
Nabih
N
Dhedin
Nathalie
N
Sirvent
Anne
A
Buzyn
Agnès
A
Rubio
Marie-Thérèse
MT
Vigouroux
Stéphane
S
Montagne
Olivier
O
Bories
Dominique
D
Roudot-Thoraval
Françoise
F
Vernant
Jean-Paul
JP
Cordonnier
Catherine
C
Klatzmann
David
D
Cohen
José L
JL
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
D053645:Interleukin-2 Receptor alpha Subunit