Hematopoietic cell transplantation (HCT) has developed from a treatment of last resort into a common medical procedure with the capability of curing complex hematologic malignancies, repairing dysfunctional hematopoietic stem cells, and inducing tolerance to solid organ allografts. Novel approaches to the use of HCT continue to emerge from basic science concepts to clinical translational activities. Over the last 4 decades, more than 1 000 000 patients have been treated with HCT, many enjoying the return to healthy and productive lives. Despite these successes, many challenges remain, as well as the opportunity to gain novel insights into immune cell biology and the capacity of immune cells to recognize malignancies. Key findings in the field have led to the development of treatment approaches such as the use of adoptive immune cell therapies with natural killer cells, T cells, regulatory cells, and other novel approaches to treat patients with serious hematological and other disorders.
At the core of HCT remains the paradox that the benefits result from the allo-immune effects characterized by the graft-versus-tumor effect that is well established and has been demonstrated by multiple lines of evidence. Initially, the finding that individuals with identical twins have less graft-versus-host disease (GVHD) but higher relapse rates than transplants performed from HLA-matched sibling donors provided novel insights into the importance of immune reactivity in HCT success. Additional studies demonstrated T-cell depletion, which reduces GVHD yet results in higher relapse rates in some series, and the dramatic finding that some patients treated with donor leukocyte infusions can revert to sustained remissions. These lines of evidence derived from careful and detailed observations of patients, as well as many laboratory-based studies, have firmly delineated the major goal of HCT of inducing an allo-immune response capable of recognizing even resistant hematologic disorders. Despite this, relatively little is known about the targets of these allo-immune effects and how integrally related these immune reactions are to the major nemesis of HCT, namely that of GVHD. The field remains firmly at the intersection between basic scientific inquiry and clinical treatment of patients with complex and often life-threatening hematologic malignancies or genetic disorders. For many of us, this tight linkage between science and medicine has been a major motivating force for our own careers and hopes that with further knowledge, not only can the field be improved resulting in better outcomes for our patients, but also that this potentially life-saving treatment concept can be applied more broadly to a variety of different clinical settings.
In this Review Series, experts from around the world review important concepts in the field, updating where we are in 2014 and where we need and hope to go in the future. Recent major advances such as the development of nonmyeloablative and reduced intensity preparative regimens and the more routine and established introduction of alternative donor sources such as umbilical cord blood and haploidentical transplantation have led to a broad opening of the field to appropriate patients of nearly any age, ethnicity, and family history. Despite these advances, we continue to struggle with GVHD and immune incompetence, resulting in a high risk of opportunistic infections until the hematopoietic graft is firmly established. New concepts developed from animal modeling where key concepts have been developed using both canine and murine systems, development of biomarkers, and drug development of novel targets brings hope that further advances are on the horizon.
The reviews in this series include the following:
Kate A. Markey, Kelli P. A. MacDonald, and Geoffrey R. Hill: “The biology of graft-versus-host disease: experimental systems instructing clinical practice.”
Boglarka Gyurkocza and Brenda M. Sandmaier: “Conditioning regimens for hematopoietic cell transplantation: one size does not fit all.”
Natasha Kekre and Joseph H. Antin: “Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does not exist.”
Shernan Holtan, Marcelo Pasquini, and Daniel J. Weisdorf: “Acute graft-versus-host disease: a bench-to-bedside update.”
Gérard Socié and Jerome Ritz: “Current issues in graft-versus-host disease.”
We hope that you find this Review Series to be informative and of interest to your scientific research, clinical translational studies, and clinical practice.
