GVHD Insights Point to Importance of Immunometabolism to Control Disease

According to the study authors, a growing number of findings from preclinical studies have suggested a focus on immunometabolism to modulate alloreactive donor T cell responses to control graft-versus-host disease (GVHD) and promote graft-versus-tumor effect.

As researchers continue to look for ways to advance treatment of acute and chronic graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), new research is highlighting insights coming from preclinical and clinical studies and recent learnings from novel therapeutic targets using metabolomics.

According to the study authors, a growing number of findings from preclinical studies have suggested a focus on immunometabolism to modulate alloreactive donor T cell responses to control GVHD and promote graft-versus-tumor (GVT) effect.

They write: “Metabolic intervention with pharmacological agents can harness regulatory cell potency and stability impairing pathogenic alloreactive donor T cell responses. Metabolic reprogramming of ex-vivo immune cells by gene editing technologies could be employed to target specific cell populations in an effort to enhance adoptive cellular therapy.”

The researchers explain that the metabolic reprogramming of T cells and other cell types may aid in quickly producing ATP in an environment of limited substrate or by promoting glycolytic intermediate flux into biosynthetic pathways.

The study also emphasizes a need for future studies focused on determining the relationship between metabolism and GVHD, as well as the metabolism-microbiota axis, to help determine appropriate therapeutic targets and explore the safety and long-term effects of metabolic interventions on the risk of infection and GVL.

These approaches, they say, may pave the way for both a clearer understanding of metabolic pathways in immune cell dysregulation during allo-HSCT and the emergence of novel treatments for preventing and treating GVHD.

“A challenge in the field is the lack of clinical trials focused on metabolic interventions in GVHD,” highlighted the researchers. “While there are retrospective metabolomic studies reporting correlative changes in host and microbiota-derived metabolites with aGVHD, prospective trials in various patient groups and treatment regimens are needed to identify metabolic pathways and targets for interventional trials.”

According to the researchers there is just 1 trial registered with clinicatrials.gov that is specifically aimed at prospectively altering metabolism for aGVHD prophylaxis. There are none registered for acute GVHD prophylaxis and none registered for chronic GVHD prophylaxis or treatment.

Reference

Mohamed F, Thangavelu G, Rhee S, et al. Recent metabolic advances for preventing and treating acute and chronic graft versus host disease. Front Immunol. Published October 12, 2021. doi: 10.3389/fimmu.2021.757836