Cellular therapy for hematology malignancies: Allogeneic hematopoietic stem transplantation, graft-versus-host disease, and graft versus leukemia effects

Abstract

The ability of allogeneic hematopoietic cell transplantation (HCT) to cure hematologic malignancies is widely recognized. An important therapeutic aspect of HCT in eradicating malignant cells is the graft-versus-leukemia (GVL) effect. But the GVL effect is closely associated with graft-versus-host disease (GVHD) the major complication of HCT. GVHD remains the major barrier to the wider application of allogeneic HCT for a variety of diseases. GVHD occurs in two forms, acute and chronic, and both are associated with GVL effects. Recent advances in the understanding of genetic polymorphisms, the chemo-cytokine networks, several novel cellular subsets including regulatory T cells, and of the direct mediators of cellular cytotoxicity have led to improved understanding of these complex processes. Animal studies show that modulating several mediators of the complex GVHD cascade may be able to reduce the undesirable inflammatory aspects of GVHD while preserving the benefits of GVL. However, most of the laboratory observations remain to be studied in well-controlled clinical trials. Multiple cellular effectors may be involved in GVL, although donor T cell recognition of host antigens is an important element of this process. Cellular immunotherapy such as donor leukocyte infusion offers a strategy for separating GVHD and the GVL effect. Both experimental and clinical data suggest that post-transplantation cellular immunotherapy can be performed relatively safely and effectively, and optimization of patient selection, cell dose, and timing of administration may all serve to limit toxicity and enhance the potential GVL effects.