Schematic illustration of a DROP-CAR, copyright Leo Scheller.
Chimeric antigen receptor (CAR) T-cell therapy is based on engineered immune cells that find and destroy cancer cells. However, sometimes these cells also attack healthy tissues, causing side effects. An international team of researchers has now developed a system to control T-cell binding to other cells by an approved small molecule drug.
Researchers at the Leibniz Institute for Immunotherapy (LIT), Ecole polytechnique fédérale de Lausanne (EPFL), ETH Zürich, and Lausanne University have developed a system to make CAR T-cell therapies safer and more controllable. Published in Nature Chemical Biology, the new work introduces DROP-CAR (Drug-Regulated Off-switch PPI CAR) systems to remotely control CAR T-cell activity using venetoclax, a clinically approved drug already in use for blood cancers. This technology can precisely modulate therapeutic function of CAR T cells, if adverse effects emerge.
"CAR T-cell therapy has revolutionized treatment for certain blood cancers, but progress for many other tumors is held back by safety concerns," explains Dr. Leo Scheller, lead author and head of the research group Structural Biochemistry at the LIT. “New tools like the DROP-CAR take steps towards bringing new treatments to the clinic that might otherwise be too risky."
Control through protein-protein interactions
A CAR contains an outer part sticking out of the T cell that recognizes cancerous target cells, and an intracellular part that signals to the T cell to kill, once activated. However, sometimes healthy cells are mistakenly targeted by the same mechanism. The DROP-CAR splits the two receptor parts into two separate components. Adding the drug venetoclax causes the outer part to fall off, prohibiting T cells from binding to other cells in the first place. This method is expected to increase safety of potential CAR T-cell therapies.
Original publication: Scheller, L., Giordano Attianese, G.M.P., Castellanos-Rueda, R. et al. Drug-controlled CAR T cells through the regulation of cell–cell interactions. Nat Chem Biol (2026).
Bron: idw online