The potential role of gamma delta T cells after allogeneic HCT for leukemia

Allogeneic hematopoetic stem cell transplantation (HCT) offers an option for patients with hematologic malignancies, in whom conventional standard therapies failed or are not effective enough to cure the disease. Successful HCT can restore functional hematopoiesis and immune function, and the new donor-derived immune system can exert a graft-versus-leukemia (GVL) effect. However, allogenic HCT can also be associated with serious risks for transplantation-related morbidities or mortalities such as graft-versus-host disease (GVHD) or life-threatening infectious complications. GVHD is caused by alloreactive T lymphocytes, which express the alpha beta T-cell receptor, whereas lymphocytes expressing the gamma delta T-cell receptor are not alloreactive and do not induce GVHD but can exhibit potent antileukemia and anti-infectious activities. Therefore, gamma delta T cells are becoming increasingly interesting in allogeneic HCT, and clinical strategies to exploit the full function of these lymphocytes have been and are being developed. Such strategies comprise the in vivo activation of gamma delta T cells or subsets after HCT by certain drugs or antibodies or the ex vivo expansion and manipulation of either patient derived or donor-derived gamma delta T cells and their subsets and the adoptive transfer of the ex vivo-activated lymphocytes. On the basis of the absence of dysregulated alloreactivity, such approaches could induce potent GVL effects in the absence of GVHD. The introduction of large-scale clinical methods to enrich, isolate, expand, and manipulate gamma delta T cells will facilitate future clinical studies that aim to exploit the full function of these beneficial nonalloreactive lymphocytes.