Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versushost disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and lowdose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

“…In addition to the GVHD treatments discussed above targeting specific T cell activation signals, cellular therapies for GVHD benefit from being able to target multiple pathways at once. Cellular therapies like Treg and mesenchymal stromal cell (MSC) were both studied in xenogeneic transplant models before moving into late stage clinical trials ( 134 , 135 ). While the suppressive mechanism(s) identified for each cellular therapy are distinct, one common theme is the secretion of anti-inflammatory cytokines (e.g.…”

“…While the suppressive mechanism(s) identified for each cellular therapy are distinct, one common theme is the secretion of anti-inflammatory cytokines (e.g. IL-10, IL-35, TGF-β and PGE2) with only a limited role identified for inhibitory ligand/receptors ( 134 , 135 ). Phase I trials using these adoptive therapies have shown promising but mixed results, most likely due to the inefficiencies and irregularities involved with ex vivo expansion of these cells (NCT04678401) ( 136 ).…”

Insights into mechanisms of graft-versus-host disease through humanised mouse models

“…To meet this growing need to improve patient outcomes following allogeneic HSCT different approaches and new combinations of the above GVHD therapies continue to be investigated. Moreover, research continues to investigate a broad range of new therapeutics including, but not limited to, co-stimulatory blockade with abatacept (CD28 blockade), targeting cytokines using etanercept [tumour necrosis factor (TNF-α) blockade] and tocilizumab (IL-6R blockade), use of the kinase inhibitor ruxolitinib (JAK 1/2 inhibition) or the anti-proliferative reagent azacitidine (DNA-methyltransferase inhibition), glycoprotein targeting with sitagliptin (CD26/dipeptidyl peptidase-4 inhibition), and regulatory therapies including low dose IL-2 and transfer of Tregs [ 27 ].…”

Therapeutic Perspectives of CD26 Inhibitors in Imune-Mediated Diseases

“…Therefore, the targeting of CD26 in T cells has the potential to be useful in studies of GVHD. CD26 + T cells infiltrate the skin and intestinal tract in clinical GVHD, and these results strongly suggest that CD26 assists T-cell migration across the endothelial barrier, as well as a role for CD26 + T cells in the pathophysiology of GVHD [ 52 , 53 ]. In patients undergoing hematopoietic stem cell transplantation, gliptins are capable of attenuating a cleavage of Chemokine CXCL12, thus facilitating the homing and engraftment of donor cells.…”