Designing better T cells for use in stem cell transplantation

Donor stem cell/bone marrow transplantation (allo-SCT/BMT) is an important curative therapy in the treatment of blood cancers, however its application is limited by serious complications such as graft-versus-host disease (GVHD) that have a significant impact on patient mortality and quality of life. Early inflammatory responses during preparative transplant conditioning initiate a cascade of adaptive immune responses that manifest as acute and/or chronic tissue damage in >50% of transplant recipients. GVHD treatment options are relatively limited and focused on immunosuppression and steroidal therapy, which are problematic due to opportunistic infection and refractory disease, therefore new therapies are urgently needed. Donor-derived T cells are known to be the key drivers of GVHD pathology but are also critical to maintain ongoing anti-tumour immunity, also known as Graft-versus-leukaemia (GVL) effects, which prevent cancer relapse in these patients. Identifying novel ways to target GVHD whilst maintaining GVL is key to improving patient outcomes. We propose that in vivo screening of potential therapeutic targets via manipulation of donor T cells pre-transplant will accelerate therapeutic development in this area.

In this study, we will utilise recent advances in CRISPR-mediated gene therapy to modulate T cell function in naïve primary T cells for allo-SCT.

This will involve optimisation, testing and validation of CRISPR gene editing of novel targets in naïve mouse T cells in vitro prior to transplant into allogeneic mice.

Students will develop new skills in techniques relevant to immunology research such as immune cell isolation, gene modification and exposure to in vivo models of inflammatory disease. This research has the potential to develop novel treatment approaches for blood cancer patients.