Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity

Abstract

Chimeric antigen receptor (CAR)-redirected cellular therapy is an attractive modality for cancer treatment. We hypothesized that allogeneic CAR-engineered CD45RA-negative T cells can control cancer and infection without the risk of graft-versus-host disease (GVHD). We used CD19 + MLL-rearranged leukemia as prototype because it is an aggressive and generally drug-resistant malignancy. CD45RA - cells that were transduced with anti-CD19 CAR containing 4-1BB and CD3ζ signaling domains effectively lysed MLL-rearranged leukemia cell lines and primary blasts in vitro. In a disseminated leukemia mouse model, CAR + CD45RA - cells significantly reduced leukemia burdens and prolonged overall survival without GVHD. CAR + cells were sustainable in blood, and all the treated mice remained leukemia-free even after they were re-challenged with leukemia cells. Despite the transduction process, CD45RA - cells retained recall activity both in vitro and in vivo against human pathogens commonly found in cancer patients. In comparison with CD45RA + cells, CD45RA - cells showed less allogeneic activity in mixed leukocyte reactions and in mouse models. Thus, the use of CAR + CD45RA - cells can separate GVHD from graft-versus-malignancy effect and infection control. These cells should also be useful in nontransplant settings and may be administered as off-the-shelf third-party cells.