A combination of two drugs could improve outcomes and reduce the need for toxic chemotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), the commonest cancer in childhood and one that can be particularly difficult to treat in older patients, according to Cambridge scientists.
Although the research has so far only been conducted in cell lines and mice, the team is seeking funding to begin clinical trials in patients shortly.
More than 500 people a year in the UK are diagnosed with B-ALL, many of whom are children, where it makes up 40% of all childhood cancers. Although the disease is curable in the majority of younger patients, the treatment requires over two years of chemotherapy, leaving the patient susceptible to infections and experiencing toxic side effects including bruising and bleeding, hair loss, nausea and vomiting, as well as potential long-term damage notably to nerves, joints and the heart. Outcomes tend to be much poorer for older children and adults.
Dr Simon Richardson from the Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, said: "Every week, I see adult patients who are undergoing treatment for this incredibly aggressive form of leukaemia, and although the chemotherapy can cure many of them, the side effects are often really challenging. We need to find treatments that are kinder and more effective."
In recent years, new treatments have begun to emerge, including bone marrow transplants and immunotherapies such as CAR-T cell therapy, but these also come with significant side effects and are expensive.
Now, in research published today in Nature Communications, a team led by Dr Richardson and colleague Professor Brian Huntly has developed a new treatment with the potential to be less toxic than current treatment and to be effective in all age groups.
B-ALL is characterised by malignancies of early-stage B-cells. These are cells produced in our bone marrow that play an important role in our immune systems, producing antibodies to protect us from infection. However, in B-ALL, the body produces an overabundance of these cells that build up in our bone marrow and stop healthy blood cells from developing. They can also spread to other parts of the body.
"There's a constant stream of these cells coming out through the bone marrow into the immune system," said Dr Richardson. "The ones that cause cancer are very primitive and not yet useful. They build up in the bone marrow and then often move around the body, such as invading into the brain where they can hide from chemotherapy. It's a really nasty kind of cancer."
Treatments for B-ALL focus on killing these malignant B-cells. The approach being trialled by the team at the Cambridge Stem Cell Institute involves the use of two oral drugs in tandem, venetoclax and inobrodib.
Venetoclax is already used to treat a related condition, acute myeloid leukaemia (AML). It works by targeting the protein BCL2 within the B-cells, causing them to die through a process of 'programmed cell death' known as apoptosis. However, venetoclax is not consistently effective in B-ALL.
The team was studying another gene called CREBBP, certain mutations of which contribute to disease progression and are also associated with resistance to chemotherapy in B-ALL. They found that when CREBBP is switched off, it leads to a rewiring of the fat metabolism of B-cells. When BCL2 activity is subsequently inhibited – for example by using venetoclax – it leads to cell death, but by a completely different process known as ferroptotic programmed cell death. This is where the cells are no longer able to protect themselves against damage to the fats in their membranes, causing the cells to become overwhelmed and break down.
The researchers used a new drug called inobrodib, developed by CellCentric, a University of Cambridge spinout company, to switch off CREBBP in human and mouse models of B-ALL. Combining it with venetoclax potently killed early-stage B-cells, even those cells that carried a genetic mutation making them resistant to venetoclax treatment alone.
Professor Brian Huntly, also from the Cambridge Stem Cell Institute and Head of the Department of Haematology, said: "These are very promising findings, and even though our work was only in mice, we're optimistic that we will see similar effects in patients. Venetoclax and inobrodib have already been used together in an early-stage clinical trial for AML, so we know they are safe to use. We now want to trial our approach in adults and teenagers with B-ALL."
B-cells are a vital part of the immune system, and although this drug combination will destroy the cells while the patient is on treatment, the body should begin producing them again once treatment is stopped. This makes this approach potentially much safer than CAR-T cell therapy, for example, which can permanently eradicate the body's ability to produce B-cells.
Dr Richardson, who is also a Fellow at St Catharine's College, Cambridge, added: "The good news is that the cost of venetoclax is expected to fall in coming years with the introduction of generic alternatives, making its use much more cost effective."
Professor Huntly and Dr Richardson are Honorary Consultant Haematologists at Addenbrooke's Hospital, Cambridge. Professor Huntly is Chair of the Haematology Service at Cambridge University Hospitals NHS Foundation Trust.
The research was largely funded by Cancer Research UK and Leukaemia UK.
