Funded by Bristol-Myers Squibb
Treatment for children with relapsed leukemia has been transformed by the use of chimeric antigen T-cells (CAR-T), which use a patient’s own immune cells after they’ve been engineered to kill leukemia cells by recognizing specific proteins on cells. Yet, about a third of children will again suffer relapse after CAR-T cell treatment when the leukemia cells stop expressing the target protein on the surface of the cell. This makes the leukemia cell invisible to the CAR-T cells and blunts eradiation of the leukemia. This occurs when the leukemia cells express alternative forms of the target protein. It is not well understood if these alternative forms only occur after pressure of the CAR-T treatment or if they exist already within the patient’s cells and are only revealed after CAR-T treatment. There is suggestion that healthy cells express the alternative protein forms as well. There is need to better understand what healthy cells express the variant protein forms, what their role is in normal cell biology and if leukemia cells, without pressure of CAR-T targeting express these proteins. We will use novel single-cell technologies to examine healthy bone marrow cells and diagnostic leukemia cells to determine if these cells express the variant proteins and to what extent. We will examine how these variant proteins help cells to survive. Finally, we will examine samples from patients treated with CAR-T cells to determine if these cells exist before receiving CAR-T treatment and how the treatment favors emergence of resistant cells expressing variant proteins.