Projects we fund

Overview

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Most children and young adults with ALL are treated with current chemotherapy regimens. However, prolonged treatment over several years is required, which often has physical, psychological and social consequences on patients and their families. For example, in young adult leukaemia clinics, up to one third of patients are left with damaged joints due to treatment and require joint replacements at a very young age. Therefore, an important challenge in ALL treatment is how to maintain or improve the cure rates whilst reducing the side effects of treatment.

Over the past decade, new ‘targeted drugs’ have emerged to treat ALL. Targeted drugs are designed to kill leukaemia cells but leave healthy cells unharmed. Currently targeted drugs are largely only available when patients do not respond well to chemotherapy. Although most patients who relapse after chemotherapy respond to the targeted drugs and achieve remission, most patients eventually relapse and do not survive. The mechanisms of resistance to these drugs are not well understood. There is also a lack of knowledge or rationale about how to incorporate targeted drugs into upfront treatment with or ideally instead of chemotherapy.

A targeted drug currently used is Inotuzumab Ozogamicin (IO). It is a drug composed of an antibody bound to a cell-killing toxin. However, the toxin only becomes activated to kill a cell when the antibody binds to a specific antigen called CD22 on the surface of cells. CD22 is on most patient’s leukaemia cells but not on the vast majority of healthy cells, making it more targeted than chemotherapy. Professor Cristina Lo Celso and her team plan to determine the mechanisms of resistance to IO, a targeted drug that has few side effects and induces remission in 70-80% of patients with ALL after chemotherapy fails. However, most patients eventually relapse after this treatment for unclear reasons. Professor Lo Celso’s team want to determine how the leukaemia cells that survive after IO are different to the vast majority of leukaemic cells that are killed. The team predict that, as with chemotherapy, ‘healthy normal’ bone marrow cells are co-opted to protect the surviving leukaemia cells and the leukaemia cells use this help to alter their metabolism, enabling them to survive.

What difference will this project make?

The ultimate aim of this project is to identify treatment combinations that are as or more effective than current chemotherapy but with much fewer and less serious side effects. This project aims to determine the mechanisms of resistance to Inotuzumab Ozogamicin (IO), a targeted drug that has few side effects and induces remission in 70-80% of patients with Acute Lymphoblastic Leukaemia after chemotherapy fails and find ways to prevent this happening. The team plan to test these ideas by directly visualising via a microscope the interaction of leukaemia cells with ‘healthy normal’ bone marrow cells in live anaesthetised mice models before and after IO treatment.

The project will also compare the genetics and metabolism of the leukaemia cells before and after IO treatment to determine how the metabolism of the leukaemia cells change to survive. This will enable the identification of drugs that might work in combination with IO to overcome the resistance mechanisms identified. This may include the addition of drugs known to target or inhibit the protection from the ‘healthy normal’ cells and drugs that target aspects of a cancer cell’s metabolism. This would then provide a rationale to take these treatment combinations forward to the clinic to treat patients.