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

Immunological effects of donor lymphocyte infusion for treatment of recurrent malignancy after allogeneic hematopoietic cell transplantation can be enhanced by depleting T regulatory cells in the infused cells and in the recipient. Regulatory T Cells Interfere with Graft-Versus-Tumor Effects Patients search for organ donors who are close genetic matches to avoid immune reactions. But sometimes a little immune activation is a good thing. Hematopoietic stem cells in the form of bone marrow are often used to treat blood cancers, and the donated cells not only engraft in bone to provide a source of healthy blood cells but also contain T cells that attack and destroy any remaining cancerous cells. This graft-versus-tumor effect is also harnessed when such patients suffer a relapse and donor T cells are infused into the patient. These infusions often fail to quell the malignancy, however. The reason for failure, Maury et al. have now shown, is that the donor cells can often include regulatory T cells (Tregs), a class of T cells that dampens the immune response. Removing these cells before the infusion markedly improved the graft-versus-tumor effect and the patients’ survival. The beneficial graft-versus-tumor effect of transplantation can be accompanied by the not-so-desirable graft-versus-host disease. Like the transplanted T cells that perceive cancer cells as foreign, T cells can also attack the host’s skin, liver, intestinal lining, and other internal organs—a condition that is serious but can be treated. The authors of this study used the presence of graft-versus-host disease as a sign that there were active, functioning T cells that also provided graft-versus-tumor effects. They treated 17 patients with relapsed blood cancer who had previously received an infusion of lymphocytes and had neither clinical manifestations of graft-versus-host disease nor control of their malignancy. After receiving a new infusion of lymphocytes from which the Tregs had been removed, two of the patients developed graft-versus-host disease for the first time in their transplant history. Hypothesizing that this low rate of response was a result of Treg cells present in the recipient, they treated four of the patients who needed more infusions with the same Treg-depleted cells but now infused them immediately after recipient Tregs were eliminated with lymphopdepletive chemotherapy. These four patients, all of whom had Hodgkin’s lymphoma, reacted to the infused cells by developing graft-versus-host disease, a sign that the infused cells were likely attacking the tumor cells as well. When the whole group was assessed 1 year after treatment, the patients who had experienced a graft-versus-host reaction after cell infusion were found to have survived longer, likely a result of successful immune control of the cancer cells by the infused Treg-depleted lymphocytes. This preliminary study shows that depleting donor lymphocytes of inhibitory regulatory T cells can be a safe and effective way to free active T cells from inhibition so that they can fight cancer cells in the recipient. Further studies are needed, but this seemingly inappropriate encouragement of immune reactions in transplant recipients may prove a boon to patients with blood cancers. 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.