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.

FOXP3+ regulatory T cells and their functional regulation

“…[81][82][83] On the other hand, a clinical trial has been launched to test whether Treg-depleted donor lymphocyte infusion improves graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation. 84 Their results indicated that donor lymphocyte infusion is a safe approach to induce acute graft-versus- Figure 1 Identified enzymes that are responsible for the post-translational modifications of FOXP3 and their corresponding modified residues in human FOXP3. Acetylation of FOXP3 at K263 and K268 by the acetyltransferase p300 stabilizes FOXP3 and promote its activity, while SIRT1 modulates the reciprocal modification.…”

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

“…Another clinical study 25 from Paris evaluated the effect of LD chemotherapy combined with Treg-depleted DLI. A total of 17 adult patients with malignancy relapse after allo-HSCT were studied, and two of them developed GVHD after their first Treg-depleted DLI (2 × 10 7 CD3 + cells/kg) and experienced a longterm remission.…”

“…20,23 Lymphodepletion followed by DLI Recently, lymphodepleting (LD) chemotherapy with fludarabine (Flu) and/or CY before the injection of donor lymphocytes has been used to modify the immune environment for enhancing the effectiveness of DLI, which is suggested to be associated with the suppression of regulatory T cells (Treg cells) during the LD process. [24][25][26] Miller et al 27 pioneered the LD approach in the context of DLI after allo-HSCT. The dosage of CY was 50 mg/kg once on day − 6 accompanied with Flu 25 mg/m 2 for five consecutive days (−6 to − 2) and then donor lymphocyte was infused in a fixed high dose of 1 × 10 8 CD3 + cells/kg, given 48 h after the last Flu dose.…”

Immunothérapie des cancers : une lueur au bout du tunnel ?

“…Pour le blocage des réponses régulatrices, il n'existe pas actuellement de molécule capable d'éliminer transitoirement les Treg, mais d'intenses recherches sont poursuivies dans ce domaine. La préparation de lymphocytes déplétés ex vivo en Treg avant leur réinjection chez un patient préalablement déplété de ses lymphocytes est possible, quoique lourde, et nous avons récemment montré son efficacité pour le traitement de tumeurs hématologiques [15]. Pour les effecteurs, l'équipe de Carl June, de l'université de Pennsylvanie, a produit des lymphocytes T génétiquement modifiés pour exprimer un anticorps spécifique des cellules tumorales couplé à la molécule stimulatrice CD137.…”