CAR-T therapy can cure some leukaemias, but the cancer often returns because the engineered immune cells stop working inside the bone marrow. The problem is that leukaemia inflames the bone marrow’s supporting cells, and this inflammation may disable the CAR-T cells before they finish their job. Researchers do not yet understand exactly how that inflammation arises or how it interferes with the immune cells. This project aims to map those interactions. The researcher will first use a mouse model of leukaemia to track how bone marrow inflammation develops and how it affects CAR-T cells. Then, by analysing microscopic images of bone marrow, they will pinpoint where CAR-T cells sit and which other cells they touch—working with mathematicians to quantify those contacts. Finally, they will test ways to preserve CAR-T function in a lab-grown human bone marrow organoid. If the work succeeds, it could create a pipeline for designing next-generation CAR-T therapies that resist the marrow’s inflammatory environment. That would mean fewer relapses for patients with blood cancer. The researcher also plans to work directly with patients to communicate these ideas clearly to the public.
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Some people with leukaemia can be cured with a new treatment called chimeric antigen receptor T cells (shortened to ‘CAR-T’). CAR-T therapy works by modifying a patient’s own immune cells (called T cells) to display a CAR on their surface which the cell uses to detect leukaemia. CAR-T cells are then infused into the patient where they seek out and destroy the cancerous cells. Although the treatment usually works well initially, the leukaemia can return because the CAR-T stop working. If we could fix this problem, CAR-T would have a better chance of curing the patient. For CAR-T cells to work, they must find the leukaemia in the bone marrow. The bone marrow is a very complex organ, with blood-forming cells as well as other cells that provide a supporting function. We have found that leukaemia causes inflammation in the bone marrow, especially in these supporting-type cells. It is possible that some of these inflammatory changes may stop the CAR-T from working. In this proposal, I will seek to better understand how bone marrow inflammation arises and how it affects CAR-T cells. First, using a model of CAR-T treatment of leukaemia in mice, I will identify how bone marrow inflammation arises and then assess how it affects the CAR-T cells. Second, I will analyse microscopic images of bone marrow to understand where CAR-T cells are located and with which kinds of cells they interact. In these experiments, I will work with mathematicians to measure theses interactions accurately and to identify those which are of most interest. Third, I will use a test tube model of human bone marrow (called an ‘organoid’) to test possible ways in which CAR-T function can be preserved better. In this way, I hope to create a pipeline for the design of new CAR-T based therapies that can be used in further research. I also hope to work with patients to find innovative ways of communicating these ideas and their relevance to individuals with blood cancer and the wider public.
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