Significance: Despite the unprecedented antileukemic response demonstrated in recent clinical trials, the inability to control the potent chimeric antigen receptor (CAR)—T-cell activity has resulted in several serious adverse incidents. Herein, we demonstrate that a switch-mediated CAR-T approach enables the titration of engineered T-cell antitumor activity, which was observed to be highly advantageous in reducing treatment-related toxicities in vivo. Moreover, we show that the use of optimized antibody-based switches readily enables a single CAR construct to target different antigens, indicating its potential application to treat tumor escape variants and heterogeneous tumors expressing distinct tumor antigens. Our data support the safe application of this potent immune cell-based therapy to target other types of cancer, including solid tumors, as well as nononcology indications.