Immunologic Outcomes of Allogeneic Stem Cell Transplantation: Graft-Versus-Host and Graft-Versus-Leukemia Responses and Implications for Future Therapy

Abstract

Allogeneic stem cell transplantation allo-HCT) is a procedure with the potential to cure many malignant and nonmalignant diseases. The adoptive transfer of a donor immune system into a transplant recipient can result in allorecognition and reactivity of donor immune cells against host target tissues. This can lead to an immune attack against normal tissues in the recipient graft-versus-host disease, GVHD) but also against the neoplastic cells themselves graft-versus-tumor effect, GVT). While GVHD has long been recognized as a signifi cant cause of morbidity and mortality after allo-HCT, there has been little progress in advancing the standards of care for GVHD prophylaxis and therapy, which have remain unchanged for more than two decades. Given the more recent recognition that much of the curative benefi t of allo-HCT results from the GVT effect, rather than from the cytoreductive effects of conditioning chemotherapy, multiple strategies to take advantage of the GVT effect that aim to limit morbidity and mortality due to GVHD are under investigation, including cellular therapies employing the use of native or engineered graft populations enriched for antitumor responses, and employing donor lymphocyte infusions. Another critical question is how strategies to prevent and/or treat GVHD may be designed to limit the suppression of benefi cial T cell responses against pathogens critical to limiting infections in the post-HCT setting. Research in murine models and human subjects has uncovered a great deal regarding the mechanisms of GVHD initiation and persistence, including clinical factors and graft constituents responsible for the acute and chronic forms of GVHD. A variety of cellular mediators, from antigen-presenting cells to effectors, including alloreactive T cells and B cells, have been characterized. Regulatory populations, including CD4+ regulatory T cells and invariant NKT cells, have also been shown to be capable of ameliorating GVHD intensity and survival in model systems. Given this clearer understanding of GVHD pathophysiology, a variety of novel clinical strategies are in development, from those utilizing classical inhibitors of T cell reactivity, to monoclonal antibody therapies to more novel approaches targeting specifi c signaling pathways in T cells and other mediators of infl ammation. Recent meaningful progress has also been made in approaches using adoptive cellular therapies to decrease GVHD while maintaining or specifi cally augmenting GVT responses. These strategies bring promise for a future wherein more patients can receive allo-HCT for both malignant and nonmalignant diseases, with reduced rates of complications and improved overall survival.