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.
Project Update 2022: We have developed a strategy to make an off-the-shelf cell therapy that can effectively fight acute lymphoblastic leukemia (ALL) in patients receiving a specialized stem cell transplant. First, the stem cell transplant is manipulated to deplete cells that allow transplant to patients who are not fully “matched”, thus greatly expanding the number of patients who can benefit from this life saving therapy. However, the depleted cells are also those with anti-leukemic function, a feature that can be further improved when these cells are also engineered to express a protein called CD19, which has highly effective anti-leukemia fighting functions. Thus, in a second strategy, we have developed a method to manipulate these discarded cells to: 1. maintain the anti-leukemic activity, 2. improve the anti-leukemic function by expressing CD19 and 3. remove the features on the cells that make them appear foreign to the recipient. These cells can then be administered to the patient with the goal of improving outcomes in ALL transplant recipients. We are currently performing pre-clinical scale up of the manufacture of the cells to support clinical manufacture with the goal of submitting an IND and initiating a phase 1 clinical trial.
