Introduction to a review series on pathophysiology and treatment of acute GVHD

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative approach for a large group of hematologic malignancies. The therapeutic success of allo-HCT is hampered by acute graft-versus-host disease (aGVHD), which leads to high mortality.¹  For several decades little progress has been made in treating aGVHD, with corticosteroids being the mainstay of first-line therapy. Recent preclinical and clinical studies have elucidated the role of the intestinal microbiome in the pathogenesis of aGVHD and the efficacy of cellular therapy and kinase inhibitor–based strategies in treating it. These reports have led to clinical trials for aGVHD treatment that rely on kinase inhibition strategies, microbiome transfer studies, cellular therapies, targeting of cytokines and costimulation, protease inhibitor studies, and tissue regenerative approaches.

The following series of reviews describes these major novel developments in the field of aGVHD:

• Hind Rafei and Robert R. Jenq, “Microbiome-intestine cross talk during acute graft-versus-host disease”

• Carlijn Voermans and Mette D. Hazenberg, “Cellular therapies for graft-versus-host disease: a tale of tissue repair and tolerance”

• Geoffrey R. Hill and Motoko Koyama, “Cytokines and costimulation in acute graft-versus-host disease”

• Tomomi Toubai and John Magenau, “Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease”

Several independent groups have shown that the commensal intestinal microbiome undergoes major changes in composition and diversity after allo-HCT, which is generally termed “dysbiosis.” The article by Rafei and Jenq reviews different reports on the connection between dysbiosis and intestinal aGVHD as well as causative factors for this connection. In particular, the interactions between the microbiome and the intestinal immune system, intestinal stem cells, and Paneth cells are discussed in the context of aGVHD. Novel approaches to overcome dysbiosis, such as fecal microbiota transfer strategies, as well as the risk of probiotic-related bacteremia and considerations for a more selective choice of antibiotics are also covered by the authors.

The review by Voermans and Hazenberg discusses cellular transfer strategies that reduce aGVHD severity with a particular focus on mesenchymal stromal cells (MSCs), innate lymphoid cells, and regulatory T cells. In particular, the review covers the tissue-regenerative and immunosuppressive properties of MSCs as well as their low immunogenicity, which is highly relevant in the context of third-party MSC transfer to treat aGVHD. The results of clinical studies on cellular therapy approaches are also discussed as well as the importance of clearly defining the regulatory cell types that are transferred to treat aGVHD. For MSCs, this definition is based on surface markers and functional criteria provided by the International Society of Cellular Therapies. Also discussed are host factors that could have an impact on the success of cellular therapies such as the diversity of fecal microbiota.

In light of the great success of immune checkpoint inhibition for solid tumor treatment, the activation of immune checkpoint molecules and the targeting of costimulation in aGVHD are attractive approaches for counterbalancing the uncontrolled immune reaction. Hill and Koyama elaborate on our current knowledge of the different steps of aGVHD pathogenesis. The early phase involves endogenous alarmins derived from recipient tissue and exogenous pathogen-derived molecules, and the second phase is activation of T cells by antigen-presenting cells that prime donor T cells to recognize alloantigen. In this second phase, cytokines and costimulation as well as coinhibition play a major role. The authors connect the basic biology in mouse studies to clinical trials that use cytokines (eg, interleukin-22 [IL-22]), cytokine receptor inhibition (eg, IL-6 receptor), or activation of coinhibitory molecules (eg, CTLA4-immunoglobulin) for the treatment of aGVHD.

The pathophysiology of steroid refractory aGVHD (SR-aGVHD) is poorly understood, and patients with this disease manifestation are at high risk for nonrelapse mortality. Toubai and Magenau cover the current insight into the biology of SR-GVHD, and they observe that several early phase I/II trials for SR-GVHD treatment were promising, but so far, no phase III trial has shown superiority of the tested drug compared with best available treatment. Therefore, results of the ongoing new randomized phase III trials on SR-aGVHD are eagerly awaited. The authors propose an SR-aGVHD mechanism by which long-term use of steroids may paradoxically increase expression of toll-like receptors and NLRP3, which increase inflammation. Because prevention is better than treatment, the authors also elaborate on strategies to prevent SR-aGVHD such as post-transplant cyclophosphamide, antithymocyte globulin, CD24 fusion protein, and IL-22.

This review series presents important insights into the biology of aGVHD and translational approaches that use this knowledge to improve early diagnosis and treatment. This series also aims to provide treating physicians with an overview of novel therapeutic targets that have reached clinical testing and may change clinical care, depending on the outcome of ongoing phase III trials.