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Professor Marc Mansour and his team have found a marker on T-ALL cells called CCR9 to which they plan to develop highly specific therapeutic antibodies. Some children with T-cell acute lymphoblastic leukaemia (T-ALL) have very aggressive disease that does not respond to chemotherapy and sadly most of these children will not survive from their disease.
Development of CCR9-targeting antibody therapy for paediatric T-cell acute lymphoblastic leukaemia
Professor Marc Mansour
UCL Cancer Institute
London, WC1E 6DD
1 June 2024
36 months
£349,915.44
T-cell acute lymphoblastic leukaemia (T-ALL) is an acute leukaemia in which too many abnormal T-cells are produced in the bone marrow. Some children with T-cell acute lymphoblastic leukaemia (T-ALL) have very aggressive disease that does not respond to chemotherapy and sadly most of these children will not survive from their disease. Even if chemotherapy does work, it has severe short- and long-term side effects including life-threatening infections, heart problems, life-long risk of secondary cancers, and long-term effects on growth, puberty and fertility. A new approach which does not involve chemotherapy, called immunotherapy, has shown huge promise for a similar disease called B-cell acute lymphoblastic leukaemia (B-ALL). Antibodies are our natural defence against infection but can also be engineered to seek out and kill tumour cells. They can be armoured with toxins or made to activate our own healthy T-cells against the tumour. Such therapies are currently approved on the NHS for B-ALL, where they target a protein called CD19, and this approach is currently saving the lives of many children. Unfortunately, T-ALL cells do not have CD19 on their surface, so scientists have been desperately trying to find a protein on this type of leukaemia cell that is not on any other normal tissue.
Professor Marc Mansour and his team have found a marker on T-ALL cells called CCR9 to which they plan to develop highly specific therapeutic antibodies. The project will use CCR9 antibodies to deliver a toxin to leukaemia cells, or an alternative approach where the antibody brings healthy T-cells into contact with T-ALL cells, thereby killing them. These antibodies should not have the toxicity of chemotherapy as CCR9 is not expressed on normal cells.
In this project, Professor Mansours team plan to make a new immunotherapy approach for T-ALL by developing antibodies against CCR9 which are then either armoured with toxins or engineered to activate T-cells against T-ALL cells (known as BiTE antibodies). If successful, the team would test these antibodies in clinical trials, giving new effective options for T-ALL patients with relapsed disease and eventually using them early in therapy to spare children the short and long term toxicity of chemotherapy.
Professor Mansour is an active member of the clinical acute leukaemia service at University College London Hospital, which includes looking after patients with T-ALL. He is co-affiliated between the Institute of Child Health GOS and UCL Cancer Institute, making it possible to harness the world class facilities on both sites. Professor John Hartley is scientific lead of the UCL Experimental Cancer Medicine Centre and head of the UCL ECMC GCLP facility. He invented and patented the use of PDB dimers as ADCs, through which he founded Spirogen that was then acquired by Astra Zeneca. His PBD dimer technology is now being taken forward by ADC Therapeutics, with 10 ADCs in clinical trial, including Zynlonta, which is now FDA approved for the treatment of CD19+ lymphoma.
Dr Paul Maciocia is an academic clinical lecturer at the UCL Cancer Institute, where he specialises in the development of CAR T cell for T-ALL. He has expertise in recombinant antibody engineering including BiTEs and has developed and used multiple mouse models for immunotherapy studies. The work will be led by Professor Marc Mansour who has specific expertise in T-ALL, having researched the disease for over 15 years. His research has uncovered a new genetic basis of the disease, identifying how mutations in the ‘junk DNA’ can lead to T-ALL in some children. His group has also identified genetic mutations that can be used to help work out whether patients will respond well or not to standard chemotherapy. The team recently identified CCR9 as a novel immunotherapy target for T-ALL, and together with Dr Paul Macioicia and Dr Martin Pule (UCL Cancer Institute), developed the first CCR9-directed CAR T-cell which is now being taken to an MRC-funded clinical trial.
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