Therapeutic strategies targeting immune pathways to reduce graft-versus-host disease

Dr Debbie Watson, Group Leader of the Genetics and Immunology Research Laboratory (GIRL) in the Faculty of Science, Medicine and Health, at the University of Wollongong, Australia

Donor stem cell transplantation is a curative therapy for blood cancers. The goal of donor stem cell transplantation is to reconstitute the immune system and control any residual cancer cells in the recipient, which is known as the graft-versus-leukaemia (GVL) response.

However, the donor cells (graft) can also mount a response against the recipient (host) and attack different organs including the skin, gut and liver, which is known as graft-versus-host disease (GVHD). GVHD is a debilitating disease that occurs in more than 50% of donor stem cell transplantation recipients and can be fatal. GVHD is a T cell mediated disease.

Our research uses preclinical humanised mouse models to target immune cell pathways, including specifically targeting proliferating T cells, using purinergic signalling (P2X7) blockade and targeting proinflammatory cytokines. We have shown that using post-transplant cyclophosphamide (PTCy) which target proliferating T cells, we can delay GVHD onset and reduce organ damage. P2X7 blockade can reduce clinical scores and increase regulatory T cells. Further, we have shown that combination therapies with PTCy and P2X7 blockade or interleukin-6 receptor (IL6R) blockade using tocilizumab can improve GVHD outcomes.