For all their promise, chimeric antigen-receptor (CAR)-T cells do have their limitations. For one thing, they can inadvertently kill healthy cells along with cancerous ones—or, separately, provoke a systemic immune overreaction—causing serious and sometimes even lethal side effects. Researchers led by Ludwig Lausanne’s Melita Irving and Greta Maria Paola Giordano Attianese and colleagues at the École Polytechnique Fédérale de Lausanne reported in a February issue of Nature Chemical Biology their design and preclinical evaluation of a CAR-T cell that elegantly addresses this risk. Their construct, dubbed the DROP (for drug-regulated off-switch PPI)-CAR-T cell, can be swiftly switched off by a clinically approved cancer drug, venetoclax, and then restarted upon withdrawal of the drug. The signaling component of the CAR inside the cell is linked, via its transmembrane segment, to a protein domain on the outside of the cell carrying the computationally designed human domain dmLD3. This binds to a BCL-2 domain attached to the tumor-targeting component of the CAR. Venetoclax disrupts this protein-protein interaction (PPI), releasing the tumor-targeting component and disengaging the CAR T cell from its targeted cancer cell while preserving the T cell for subsequent therapeutic revival. The researchers show that their DROP-CAR-T cells effectively kill cancer cells and can be switched off and reactivated as intended in mouse models of cancer.
Drug-controlled CAR T cells through the regulation of cell–cell interactions
Nature Chemical Biology, 2026 February 19