TY - JOUR
T1 - CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation
AU - Maury, Sébastien
AU - Lemoine, François M.
AU - Hicheri, Yosr
AU - Rosenzwajg, Michelle
AU - Badoual, Cécile
AU - Cheraï, Mustapha
AU - Beaumont, Jean Louis
AU - Azar, Nabih
AU - Dhedin, Nathalie
AU - Sirvent, Anne
AU - Buzyn, Agnès
AU - Rubio, Marie Thérèse
AU - Vigouroux, Stéphane
AU - Montagne, Olivier
AU - Bories, Dominique
AU - Roudot-Thoraval, Françoise
AU - Vernant, Jean Paul
AU - Cordonnier, Catherine
AU - Klatzmann, David
AU - Cohen, José L.
PY - 2010/7/21
Y1 - 2010/7/21
N2 - Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T regs) 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 Treg depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of Treg-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 Treg-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 Tregs. 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 Treg 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 Treg-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy.
AB - Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T regs) 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 Treg depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of Treg-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 Treg-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 Tregs. 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 Treg 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 Treg-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy.
UR - http://www.scopus.com/inward/record.url?scp=77955642823&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3001302
DO - 10.1126/scitranslmed.3001302
M3 - Article
C2 - 20650872
AN - SCOPUS:77955642823
SN - 1946-6234
VL - 2
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 41
M1 - 41ra52
ER -