The development of GvHD prophylaxis treatment used after stem cell transplants and improved matching of donors and patients has improved clinical outcomes in patients. However, there is still much to learn about the pathogenesis of GvHD to enable the development of novel therapeutics in this setting.

Some of your work focuses on very small genetic differences between people – minor histocompatibility antigens – that can trigger immune reactions. How might these tiny differences play a big role in treatment outcomes?

They do indeed play a major role in treatment outcomes as they result in the synthesis of proteins that vary in sequence between donors and patients. These variations are small (they may, for example, only result in a single amino acid difference) but they can be capable of stimulating donor derived T-cells that have never encountered this protein sequence before.

Once stimulated, these T-cells can proliferate then mediate effects such as direct cell killing and pro-inflammatory cytokine signalling. GvHD is thought to occur when donor derived T-cells start to attack normal tissues in tissue such as the skin, liver and gastrointestinal tract.

We are trying to gain a better understanding of the protein sequences targeted by T-cells mediating GvHD to understand what triggers this side effect in a proportion of patients and to inform the future development of strategies to manage and even prevent GvHD.

Do you think vaccines have a role here?

The ability of T- cells from the donor to recognize and remove residual blood cancer cells is thought to play a major role in the curative action of SCT and is known as the Graft-versus-Leukaemia (GvL) effect. If vaccines (such as mRNA vaccines) could be developed that boost the GvL effect, then they may be useful in reducing relapse rates and improving clinical outcomes.

Key to the success of this approach is identifying the proteins capable of stimulating blood cancer specific T-cells that can mediate an effective GvL effect. This may lead to the identification of vaccine candidates for inclusion in future clinical trials in a range of different disease settings.

How close are we to selectively harnessing the benefits of stem cell transplantation in blood cancer patients without triggering GvHD?

Understanding how to achieve an effective GvL effect in patients after SCT without eliciting GvHD has been a major goal of stem cell transplant research for many years.

There is still more that we need to understand about the mechanisms of both GvL and GvHD to achieve this, but research is moving in a positive direction and picking up pace, largely due to the advent of enabling technologies such as single cell sequencing, spatial transcriptomics and advances in antigen discovery.

There have also been major advances demonstrating the feasibility of introducing new immuno-therapeutics into the clinic to accelerate the future translation of findings from discovery research into the development of novel therapeutics.