This month the CIIC Spotlight is directed at a team of our researchers led by Professor Paul Moss, Dr Ram Malladi, and Professor Charlie Craddock, which is carrying out cutting edge research aiming to exploit the immune system to cure patients with haematopoietic malignancies – or blood cancers.
Stem Cell Transplantation, or “SCT”, provides a lifeline for many patients with haematopoietic malignancies, particularly in cases where other treatments are likely to fail. The procedure, originally developed in the US in the 1960s, involves using radiation and/or chemotherapy to eliminate the cancerous haematopoietic system of the patient, after which blood stem cells from a donor are infused into the patient, to recover a healthy, cancer-free haematopoietic system.
“SCT is one of the clearest examples of the immune system’s ability to cure cancer,” explains Dr Ram Malladi, co-investigator of the study. “The power of SCT to cure patients relies on an attack mounted by incoming donor immune cells, against the patient’s tumour cells – a phenomenon known as the Graft-versus-Leukaemia effect, or GvL.” Unfortunately, however, the procedure carries a high risk of complications for the patient, because alongside the helpful GvL effect, the immune response in the patient can often become directed against healthy tissues – which in extreme cases can prove fatal. This phenomenon is known as the Graft-versus-Host Disease – or GvHD. “GvL and GvHD typically go hand-in-hand. A key aim of our research is to find ways to uncouple these two effects, and induce strong anti-tumour GvL effects without the risk of GvHD.”
Professor Paul Moss leads the scientific programme behind the study, which is funded by Leukaemia and Lymphoma Research. “One of the key questions is why some patients experience very potent GvL effects, whereas others do not and are much more likely to suffer disease relapse. We believe that genetic differences in immune response genes may underly this variability in treatment outcome,” explains Professor Moss. The team’s previous research on Birmingham SCT patients has identified just such a gene, called ULBP6, which is clearly playing a very important role – as patients with one common genetic variant have a much higher chance of disease-free survival. “The effect of differences in this gene on outcome is dramatic – and currently we are trying to determine why. If we can answer that question, it should point us to ways to safely enhance the GvL effect, which is ultimately what can cure the patient.”
A second, related area the team are studying is which proteins, or “antigens” that are expressed by the tumour are the best to target in immunotherapy approaches. Professor Moss outlined a key criterion for target selection: “As SCT is used for treatment of blood cancers, candidate target antigens should ideally be present only on haematopoietic cells – that way, we will enhance responses to tumour cells in the patient’s blood system, and spare other, healthy tissues.” This idea has led them to an antigen termed HA-1, as Professor Moss explained: “HA-1 is an attractive target antigen for two reasons – not only is it selectively expressed on haematopoietic cells, but in some cases, genetic differences in the HA-1 gene between the donor used and the patient mean that incoming donor immune cells will recognize the patient’s alternative form of HA-1 as “foreign” – increasing killing of tumour cells.”
How does Professor Moss and his team envisage increasing immune responses against tumour target antigens such as HA-1 ? “One approach we are testing, in a new clinical trial that forms part of this programme, is vaccination. We plan to vaccinate healthy individuals prepared to act as donors for SCT treatment with a DNA vaccine encoding the HA-1 gene. That way, when cells are harvested from the donor prior to infusion to the patient, the immune response against HA-1 expressing tumour cells should be much more potent.” The new trial, termed HA-1VACC, will be run by Dr Ram Malladi from the Centre for Clinical Haematology, and is due to start in late 2014. “This is an exciting time in the field of SCT,” emphasizes Professor Moss. “Our Leukaemia and Lymphoma Research-funded research programme provides us with a fantastic opportunity to answer fundamental questions about the immunology of SCT in the lab, and use the insights from these studies to design and test new immunotherapies for patients.”