Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

“…GVT effects and GVHD in allogeneic HSCT: Allogeneic HSCT is an established and a potentially curative therapeutic modality not only for high-risk (HR) HMs such as relapsed/ refractory (R/R) acute leukemia but also for several benign conditions [100][101][102]. GVHD, disease relapse, and infectious complications represent the main causes of morbidity and mortality associated with the use of HSCT [100,103].…”

“…GVHD, disease relapse, and infectious complications represent the main causes of morbidity and mortality associated with the use of HSCT [100,103]. Allogeneic HSCT bene its HMs by providing graft versus tumor (GVT) or GVL effects which are mediated by donor-derived T cells as well as NK cells [100,101,104,105]. Thus, the success of allogeneic HSCT depends upon: (1) the infusion of benign stem cells and lymphocytes that are capable of inducing GVT/ GVL effect, and (2) the ability of the engrafted immune system to remove residual leukemia or tumor cells through the GVT/ GVL effect [104,105].…”

“…DLI is an effective therapy for patients with acute leukemia relapsing postallogeneic HSCT, but the development of severe acute GVHD after DLI infusions remains an obstacle to the success of this therapeutic procedure [100]. The use of oncolytic viruses such as myxoma virus is associated with control of GVHD while preserving or even augmenting GVT/GVL effects [101]. In a murine system, adenoviral vectors have been found to stimulate NK cells and ultimately cause enhanced antitumor activity in the absence of transgene expression [110].…”

Advances in Hematopoietic Stem Cell Transplantation

“…Based on the time frame, pathogenesis, symptoms and organ involvement GVHD can be characterized as acute or chronic GVHD [37]. Acute GVHD (aGVHD) occurs most frequently after engraftment, arising before day 100 post-transplant.…”

A Systems Immunology Approach to Graft-Versus-Host Disease

“…(153) However, their distinct role in GVHD is still uncertain. (154,155) The secretion of inflammatory mediators, e.g. TNF-α, IL-1, IFN-γ, and nitric oxide (NO), can also induce GVHD target organ injury independent of any cognate interaction.…”