CD4+CD25+ Regulatory T Cell Depletion Improves the Graft-Versus-Tumor Effect of Donor Lymphocytes After Allogeneic Hematopoietic Stem Cell Transplantation

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BlankSci Transl Med 21 July 2010:

Vol. 2, Issue 41, p. 41ra52

DOI: 10.1126/scitranslmed.3001302

a.. Research Article

CD4+CD25+ Regulatory T Cell Depletion Improves the Graft-Versus-Tumor Effect of

Donor Lymphocytes After Allogeneic Hematopoietic Stem Cell Transplantation

1.. Sébastien Maury1,2,*,

2.. François M. Lemoine3,4,

3.. Yosr Hicheri1,2,†,

4.. Rosenzwajg3,4,†,

5.. Cécile Badoual5,6,

6.. Mustapha Cheraï3,4,

7.. Jean-Louis Beaumont7,

8.. Nabih Azar3,

9.. Nathalie Dhedin8,

10.. Anne Sirvent9,

11.. Agnès Buzyn10,

12.. Marie-Thérèse Rubio10,

13.. Stéphane Vigouroux11,

14.. Olivier Montagne2,12,

15.. Dominique Bories1,2,

16.. Françoise Roudot-Thoraval2,13,

17.. Jean- Vernant8,

18.. Cordonnier1,2,

19.. Klatzmann3,4,‡ and

20.. José L. Cohen4,8,*‡

+ Author Affiliations

1.. 1Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital

Henri Mondor, Créteil F-94010, France.

2.. 2Université Paris-Est Créteil Val de Marne, Créteil F-94010, France.

3.. 3Department of Biotherapies, Assistance Publique-Hôpitaux de Paris,

Hôpital Pitié-Salpêtrière, Paris F-75013, France.

4.. 4Centre National de la Recherche Scientifique UMR 7211, Université Pierre

et Marie Curie Paris 06, Paris F-75013, France.

5.. 5Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital

Européen s Pompidou, Paris F-75015, France.

6.. 6Ecole Nationale Vétérinaire d’Alfort, EA4054, Paris Descartes University,

Paris F-75005, France.

7.. 7Department of Hemapheresis, Etablissement Français du Sang d’Ile de

France, Créteil F-94010, France.

8.. 8Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital

Pitié-Salpêtrière, Paris F-75013, France.

9.. 9Department of Hematology, Hôpital Archet, Nice F-06000, France.

10.. 10Department of Hematology, Hôpital Necker, Paris F-75015, France.

11.. 11Department of Hematology, Hôpital Haut-Leveque, Bordeaux F-33000,

France.

12.. 12Center for Clinical Investigation in Biotherapy, Assistance

Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil F-94010, France.

13.. 13Department of Public Health, Assistance Publique-Hôpitaux de Paris,

Hôpital Henri Mondor, Créteil F-94010, France.

1.. *To whom correspondence should be addressed. E-mail:

sebastien.maury@... (S.M.); jose.cohen@... (J.L.C.)

Abstract

Donor T cells play a pivotal role in the graft-versus-tumor effect after

allogeneic hematopoietic stem cell transplantation. Regulatory T cells (Tregs)

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

Treg-depleted donor lymphocyte infusion received a second Treg-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 Treg-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.