T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive and hard to treat cancer. CAR-T cell therapy has done an incredible job in improving survival rates for some cancer types, but it has been difficult to develop a CAR-T cell therapy against T-ALL that doesn’t also result in dangerous side-effects. Dr Marc Mansour and his team hope to produce the first CAR T-cells that can safely treat T-ALL cells without harming healthy cells.
Exploiting a novel immunotherapy target for the treatment of T-cell acute lymphoblastic leukaemia (T-ALL)
Dr Marc Mansour
UCL Cancer Institute
London WC1E 6DD
14 September 2020
T-cell acute lymphoblastic leukaemia (T-ALL) is a type of childhood leukaemia caused by the body overproducing T cells, a type of white blood cell. It is rarer but more aggressive than B-cell acute lymphoblastic leukaemia (B-ALL), does not always respond to chemotherapy and has very few treatment options when the disease relapses.
CAR T-cell therapy is an exciting new type of cancer treatment. It works by instructing healthy T cells from the body’s immune system to attack cancer cells that display a particular molecule on their surface. Research into CAR-T cell therapy so far has done an incredible job in improving survival rates for some cancer types, such as B-ALL. However, right now there isn’t an equivalent CAR‑T cell therapy for T-ALL, which is more difficult to treat this way.
One of the reasons for this difficulty is that T-ALL cells look a lot like healthy T-cells. This means that CAR T-cells would also kill healthy T-cells, which would dangerously suppress the patient’s immune system.
Dr Marc Mansour and his team have identified a protein that appears to be present in high quantities on the surface of T-ALL cells, but not on healthy T-cells. In this project, Dr Mansour and his team will first investigate exactly how much protein is present on different types of T-ALL cells and at different stages of the disease. They will then check that this protein isn’t present on any of the cells in important organs in the body, otherwise targeting it could have dangerous side effects. They have already looked at this in over 170 samples from different organs, and the results look extremely encouraging, but they will examine this further to be sure. Once this is confirmed they will develop CAR T-cells capable of recognising and targeting the protein and test how effective they are in pre-clinical models.
Although T-ALL is rarer than B-ALL, it is still one of the most common cancers of childhood. Its aggressive nature and the lack of available treatment options means that T-ALL accounts for over 30% of the childhood ALL cases that fail to achieve remission with induction chemotherapy. For children who do survive, the intensity of the chemotherapy treatment can leave them with severe short- and long-term side effects including life-threatening infections, heart problems, risk of secondary cancers, and long-term effects on growth, puberty and fertility. We need more effective and less toxic treatments against this disease.
While CAR-T cell therapy has shown great promise in treating B-ALL and is now available on the NHS, developing CAR-T cell therapy for T-ALL has proven much more difficult.
This project hopes to produce the first CAR T-cells that can safely kill T-ALL cells without also harming healthy cells. If successful, Dr Mansour and his team will next work towards developing a clinical trial for this new treatment in relapsed and hard-to-treat T-ALL.
This is a joint project by Dr Marc Mansour and Dr Martin Pule, both at the UCL Cancer Institute, combining the expertise of both research groups.
Dr Mansour is a consultant haematologist who specialises in the treatment of patients with acute leukaemia at UCL Hospital (UCLH), one of the largest malignant haematology centres in Europe. For many years, his research has focused on T-ALL, where he has been involved in discovering several of the genetic causes of the disease, particularly on how some cancer-causing genes are activated. He spent four years researching T-ALL at Harvard Medical School and the Dana-Farber Cancer Institute in Boston. His lab at the UCL Cancer Institute is investigating new ways of targeting T-ALL cells without harming healthy cells.
Dr Pule is a pioneer of CAR T-cell therapy; during his PhD studies in Baylor College in USA, he led one of the first CAR T-cell trials ever to be conducted in humans. His lab at the UCL Cancer Institute is at the forefront of developing new CAR T-cell technologies, particularly in how to make them safer and more effective, and several clinic trials are ongoing at UCLH using technology developed in his lab.