Acute myeloid leukaemia (AML) is a cancer of the white blood cells which develops in the bone marrow. It originates in marrow stem cells that develop abnormalities deep in their instruction manual, the DNA. These cells then become elusive “leukaemic stem cells”. Current chemotherapy can efficiently kill leukaemia cells in the bone marrow, but generally do not get rid of the leukaemic stem cells- this means that some time after chemotherapy, the leukaemia returns or “relapses”. These leukaemic stem cells are few and far between, and looking for them amongst the billions of other cells in the marrow is like looking for a needle in a haystack. We work on methods to find these cells and determine exactly how they have gone wrong in order to target them directly with new drugs.
Blood cancer and its treatment
About 10,000 new patients are diagnosed with blood cancer each year in the UK. We aim to improve the clinical management of these disorders by supporting collaboration between our own team and other expert groups.
STEM AND IMMUNE CELL TRANSPLANT AND CELL THERAPY
Transplanting stem cells and immune cells from a healthy donor is a well-established cellular therapy for numerous blood cancers and blood diseases. In the context of blood cancer, stem cells are harvested from the bone marrow or blood of the donor, and then infused into the patient after unhealthy bone marrow has been eliminated by chemotherapy or radiotherapy. Transplants work because the graft contains immune cells (called ‘T cells’) that can reject the blood cancer. However, T cells within the graft can also lead to immune-related side events, for example graft-versus-host disease, a complication that can cause inflammation in normal parts of the body. Prof Ronjon Chakraverty’s research group is seeking to understand how to foster the anti-cancer effects of T cells, while avoiding damage to normal tissues.
More recently, new therapies have emerged in which T cells can be modified in the laboratory to become more specific. For example, a gene can be inserted which codes for a molecule that enables the T cell to recognize and kill cancer cells. New gene-modified T cell therapies (called chimeric antigen receptor T cells or CAR-T cells) have been introduced into routine treatment for certain blood cancers, and additional CAR-T treatments are likely to be available soon. It will be important to understand why some patients respond to these treatments while others don’t, and this is an area of intensive research.
Prof Chakraverty is leading efforts at Oxford to build the infrastructure required to deliver the first-in-human trials in advanced cell and gene therapies for patients in Oxford
Lymphoid disorders
Lymphoid disorders include a wide range of blood diseases that involve cells from the immune system, known as lymphocytes. Our research covers a number of lymphoid disorders including: Hodgkin Lymphoma, B and T-cell non-Hodgkin lymphoma, myeloma (and other plasma cell disorders), chronic lymphocytic leukaemia (CLL) and multiple myeloma. Over the last few decades, our understanding of how immune system cells (lymphocytes and plasma cells) become cancerous has increased considerably. This has led to the development of targeted new therapies, some of which are already being used in routine clinical practice. However, the outcomes for patients with myeloma and relapsed lymphoma could still be improved.
Our group is leading several early trials of new treatments, particularly for B and T cell lymphomas. We are collaborating with other expert groups in the UK to test new agents that reduce inflammation in myeloma and a new anti-cancer virus. We also work closely with biotech partners, enabling them to bring some of their new treatments to patients with lymphoid cancers.
Acute Myeloid Leukaemia Research (AML)
Current projects are focused on finding out how the disease first starts and then progresses in adult AML and in Myeloid Leukaemia of Down’s Syndrome. We have established a large tissue bank of blood cell samples from patients with AML which have been screened for genetic mutations linked to the disease. We are trying to find out which faulty genes cause the leukaemia cells to multiply. If we can identify the mutant proteins that are produced by these genes, we may be able to find drugs that will block their activity and so stop the leukaemia cells in their tracks.
Children with Down’s Syndrome are at increased risk of developing AML, which appears to be linked to mutations in a gene called GATA1. The number of mutations can increase over time. We work with clinicians to identify Down’s syndrome patients with GATA1 mutations. These patients are then followed-up with regular tests to see if the numbers of gene mutations are increasing. This can aid diagnosis and guide therapy. We have collected more than 200 samples from children with Downs with a pre-leukaemic condition (TMD, Transient Myeloproliferative Disorder) and Myeloid Leukaemia of Down’s Syndrome (ML-DS) from around the world.
Myeloproliferative Disease
Myeloproliferative neoplasms (MPN) are a group of chronic blood cancers that cause increased production of bone marrow and blood cells. Types of MPN include Chronic Myeloid Leukaemia, Polycythaemia Vera, Essential Thrombocythaemia, Myelofibrosis and other rare subtypes. In the majority of cases these cancers develop and progress slowly. In addition to an increased risk of progression into advanced forms of blood cancer, MPNs can cause significant symptoms and cancer-associated complications including blood clots.
Researchers associated with Oxford Centre for Haematology are focused on understanding why MPNs arise, and the mechanisms that drive progression from chronic to advanced stage disease. To do this they apply a number of state-of-the-art scientific approaches, including developing and applying new approaches to study the gene activity and changes to the genetic code of the cancer cells. This includes approaches that enable the analysis of many thousands of cells individually, to provide the necessary resolution to study rare cell types such as the cancer-initiating stem cells and rare cells called megakaryocytes that are responsible for causing scarring or ‘fibrosis’ of the bone marrow in some patients. Their research is highly translational, focused on developing new approaches to improve outcomes for patients with MPNs. This includes methods to improve diagnosis, assessment of risk, and identifying new potential treatments as well as more clinically-relevant systems to validate and test new potential therapies.
OCH researchers are actively involved in over 25 clinical trials for new MPN treatments, in collaboration with other academic and industry partners across the UK.
Myelodysplasia (MDS)
Myelodysplasia (MDS) includes a diverse group of blood cell disorders, caused by abnormal bone marrow changes or ineffective blood cell production and development. These result in anaemia, infections and bleeding. MDS patients also have a high risk of developing acute myeloid leukaemia (AML).
Our research focuses on rare MDS bone marrow cells, known as MDS stem cells, which are responsible for the disease. Past and current research is looking at how to identify these cells in different types of MDS, and how they differ from normal cells.
Common genetic changes found in MDS bone marrow cells seem to be responsible for starting the disease as well as the progression to AML. We are using the results from our analysis of patients’ genes and blood cells to set up experiments in the lab that will help us work out how these genetic changes lead to the condition.
We are also investigating the process of normal blood cell production, in particular looking at why blood stem cells develop one way or another, as well as identifying the molecular signals that influence this decision. The better we understand normal blood development, the better we will be able to identify how this process can go wrong in leukaemia.
Finally, MDS stem cells are sometimes resistant to the drug treatments currently available, which means treatment options are very limited. We are therefore exploring novel ways to eliminate the problematic MDS stem cells in order to cure greater numbers of patients with MDS.
Myeloma
Myeloma is an incurable cancer of bone marrow-dwelling plasma cells, which interacts with its bone marrow microenvironment to cause immune suppression and bone destruction. In recent years various novel therapies have been developed that have improved survival significantly, but cure has remained elusive, and targeting these various new treatments to the patients and disease stage where they will be most effective remains a great challenge. In Oxford, we research the following areas:
1. The genetics of ‘high risk’ myelomas that have poor outcomes and develop drug resistance – we have identified certain genetic features associated with resistance to IMiD drugs, and we are working to implement targeted genetic sequencing into national trials and NHS care, to better identify patients who need treatment intensification.
2. Early diagnosis of the ‘pre-myeloma’ condition MGUS; how best to screen the population and those with pre-malignant MGUS who may need intensified monitoring and potentially intervention to prevent cancerous transformation.
3. Clinical trials of novel therapeutics. We work with a range of industry partners in delivering phase I/II trials of novel agents. Alongside the clinical trials we apply systems biology approaches to samples from patients in these trials, to look for biomarkers of response and resistance.
Blood cancer research team
Stephen Booth
Clinical Research Fellow in Lymphoma
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