A CAR against rejection: dual-targeting allogeneic T cells

In this issue of Blood, Jin et al, 1 developed a multiplexed CRISPR/Cas9edited anti-B-cell maturation antigen (BCMA)/anti-NKG2A tandem chimeric antigen receptor (CAR) T-cell product to overcome the 2 major barriers of allogeneic CAR T-cell therapy: graft-versus-host disease (GVHD) and hostversus-graft rejection (HVGR).CAR T-cell therapy has been established as a successful treatment option for diverse hematological tumors, culminating in 7 autologous US Food and Drug Administration-approved products targeting CD19 or BCMA.Despite their remarkable clinical response, CAR Tcell therapies remain constrained by complex, labor-intensive, and costly manufacturing processes that depend on autologous patient T cells and by the absence of approved off-the-shelf CAR Tcell therapies.These limitations resulted in intense efforts to develop allogeneic CAR T-cell products.However, successful implementation requires overcoming 2 fundamental immunological barriers: T-cell receptor (TCR)-mediated GVHD and host immune rejection of the infused CAR T cells by endogenous natural killer (NK) and T cells.Although HVGR leads to a rapid rejection of the donorderived CAR T cells, thus compromising or eliminating therapeutic efficacy, GVHD represents a potentially life-threatening complication in which the infused donorderived CAR T cells attack host tissues.