Steering CAR T cells to distinguish friend from foe

CD19-specific chimeric antigen receptor (CAR)⁺ T cells have demonstrated clinical efficacy and long-lasting remissions, concomitant with tolerable normal B-cell aplasia. However, many tumor-associated antigens (TAAs) are expressed on normal tissues, the destruction of which would lead to intolerable toxicity. Thus, there is a need to engineer CAR⁺ T cells with improved safety profiles to restrict toxicity against TAA-expressing normal tissues. Bioengineering approaches include: (i) targeting CAR⁺ T cells to the tumor site, (ii) limiting CAR⁺ T-cell persistence, and (iii) restricting CAR activation. We review and evaluate strategies to engineer CAR⁺ T cells to reduce the potential of on-target, off-tissue toxicity.