Enhancing Hematopoietic Stem Cell Transplantation with Genetically Modified Donor T Cells

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an efficacious therapy for patients with life-threatening leukemias, but its use has been hindered by the limited availability of donors with matching HLA. Graft manipulation by removing ?? T cells and B cells can reduce the risk for graft-versus-host disease (GvHD), but leukemia relapse still occurs in 25% of pediatric patients. A novel approach to improving stem cell transplantation is to engineer the donor ?? T cells removed from graft to express chimeric antigen receptors (CARs) targeting CD19, while simultaneously inactivating the T cell receptor (TCR). The modified T cells, with >90% loss of TCR expression and >75% expressing CD19-CAR, enabled robust suppression of leukemia without causing GvHD in xenograft animal model. Thus, deploying TCR- CAR+ ?? T cells can enhance the efficacy of ?? T cell-depleted allo-HSCT.