MICA: "Off-the-Shelf" CAR-based immunotherapy of SLE by targeting B cells and plasma cells

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Lupus is a life-long illness where the immune system produces autoantibodies to attack its own healthy tissue causing inflammation and damage to organs such as the kidney and heart. Worldwide 1 in 2000 women are affected by lupus. Yet no cure has been identified and current treatments are not well tolerated and are only partially effective. One way to effectively treat lupus patients would be to eliminate their autoreactive B cells which are known to be the source of autoantibodies. Studies in mice and humans have shown that chimaeric antigen receptor (CAR)-T cells targeting B cells successfully eliminate most of the disease manifestations achieving clinical remission. This fellowship aims to develop a new CAR-based treatment by using specialised T cells called iNKT cells. These cells are unique because they recognise lipids on the surface of B cells. Since lipids are common to all individuals, CAR-iNKT cells can be made from one healthy person and used to treat any lupus patient without the risk of harm to the patient. The main purposes of this project are i) to compare the efficacy of CAR approaches targeting B cells (using CD19 as marker) versus those targeting plasma cells (identified by BCMA); ii) to develop CAR-iNKT cells and test their of ability to treat lupus in an in vivo experimental model; iii) to explore in vitro how lupus patient B cells respond to CAR-modified cells. The proposed research will provide the pre-clinical rationale for clinical development of the most effective CAR-based immunotherapy as a potentially transformative treatment for patients with SLE.