Cancer Research UK’s Discovery Programme Award scheme provides long-term support for established researchers to pursue an ambitious and creative programme of work addressing key questions in the cancer field.
Prof Paresh Vyas has been awarded this grant to research patient responses to cancer immunotherapies, including why some develop a serious, sometimes fatal, complication called graft versus host disease. This work aims to provide the foundations for creating new safer, more effective, therapies.
Allogeneic bone marrow transplantation (allo-BMT) is the most established, curative immunotherapy for treating blood cancers. In allo-BMT, billions of human immune cells, called T cells, are infused into a patient from a healthy human donor. Some of these donor T cells recognise proteins on the surface of blood cancer cells, called peptide-HLA (pHLA) antigens, and can kill these cancer cells. This curative effect is known as graft versus leukaemia (GvL).
However, other donor T cells may recognise pHLA antigens on the patient’s normal cells, triggering a serious and potentially life-threatening complication called graft versus host disease (GvHD). GvL usually accompanies GvHD. For decades, separating these types of T cell responses – preserving anti-cancer activity while avoiding toxicity – has been a central, unsolved challenge in the field.
This new project by the Vyas Group builds on their previous study of a rare group of AML patients who were cured by allo-BMT but did not develop GvHD. In this study, researchers identified specific pHLA antigens associated with long-lasting donor T cell responses. Importantly, some of these antigens were shared across multiple patients, and for, one antigen, the team showed that donor T cells selectively recognised blood cancer cells.
The newly funded research will now take this work further. The team will use unbiased approaches to identify suitable pHLA antigen targets in primary cancer samples. They will also use diverse state-of-the-art methods to discover fundamental principles of how T cells recognise pHLA antigens and how this interaction can be harnessed to safely eradicate cancer.
Speaking about the award, Paresh said:
I am deeply grateful to CRUK for funding our work. New clinically validated targets that enable the immune system to kill cancer cells are at a premium. Our patient-based studies potentially provide fundamental discovery insight into identifying these targets and how T cells may cure cancer by recognising these targets.
Crucially, this work opens a potentially safe, under-explored, highly differentiated, immuno-oncology therapeutic target space.
Finally, by learning from cured patients how immune cells eradicate cancer with the most established curative immune therapy, we wish to provide the foundations for a new class of highly differentiated cancer immunotherapies.