Vrije Universiteit Brussel

Multiple myeloma (MM) is a cancer that occurs when plasma cells, a type of white blood cells, gain malignant characteristics that enable them to form tumors in bones and other locations like spleen. There are several treatment strategies for MM. These have considerably improved the prognosis of MM patients with many patients reaching remission for longer than 5 years. Despite vast advances in therapy, most patients ultimately relapse, making MM still an incurable disease. Consequently, there is an unmet need for novel treatment strategies that ensure long-lasting remission in other words cure. In this project, we will combine the complementary expertise of two research groups to develop a new therapy that empowers the T cells of MM patients. T cells can be considered as the most potent weapon of our immune system as they are capable of killing cancer cells. In MM, T cells of patients have already been studied as a weapon of choice against MM cells. To ensure that the T cells can be locked on their target, they have been engineered with man-made receptors, designated chimeric antigen receptors (CARs), that help the T cells to bind MM cells. Unfortunately, cancer cells such as MM cells can express proteins that exacerbate the disease among other through suppression of the immune system. Two such proteins are B7-homolog 3 (B7-H3) and high mobility group box 1 (HMGB1). B7-H3 is highly expressed on the surface of MM cells. Therefore, we propose to generate improved chimeric antigen receptors that bind B7-H3 and to engineer T cells with these man-made receptors that will activate T cells and ensure persistent cancer cell killing capacity of the T cells. HMGB1 is found in the cell nucleus but in MM is transported outside the cell where it exerts immunosuppressive activity. Therefore, we propose to make HMGB1 blocking proteins that can be delivered to T cells together with the chimeric antigen receptors, making the T cells double armed against MM cells. Last year, the European Medicines Agency authorized a first T cell-based therapy for MM, making us confident that upon success this project can be translated to the clinic, leading to a novel treatment strategy for MM patients.