Optimizing TCRαβ+/CD19+-depleted haploidentical HSCT for ALL using donor-derived genome-edited CAR T cells
Lay Summary: Blood stem cell transplantation can cure acute lymphoblastic leukemia (ALL) in children who have no other remaining treatment options. Traditionally, this has not been available for all patients because of the need for stem cell donors that are compatible (matched). Over the last decade, a novel procedure has been developed in which immune cells - called T cells - that could attack patient cells in case of a mismatched transplant, are removed from the graft before the infusion (αβ haplo-HSCT). This strategy allows transplantation from partially matched stem cell donors (i.e. haploidentical), greatly expanding the number of patients who can benefit. However, some patients still experience leukemia relapse after the transplant (~25-30%). To improve patient outcomes, scientists have developed specially adapted T cells called “CAR T cells”, by taking a patient’s own T cells and engineering them to kill only leukemia cells. We have developed an innovative approach to improve CAR T cell production and broadened its accessibility. Instead of using patient T cells, we repurpose donor T cells that are separated from the stem cells and otherwise discarded, delete the gene (TRAC) responsible of potential negative effects on the recipient’s body, and replace that gene with a new gene that reprograms the cells to target and kill leukemia cells. Using this approach, we aim to create a potent treatment for high-risk ALL, eradicating leukemic cells without increasing the risk for side effects also in those patients in whom the stem cell transplant can fail.