Rest, Reset, Repeat

Chimeric antigen receptor (CAR)–T cell therapy uses a patient's own genetically modified T cells to seek out and attack cancer cells.  By targeting specific tumor antigens, CAR-T cells are increasingly used as an effective immunotherapy in patients with hematologic cancers.  However, the cells' cancer-killing efficiency often wanes over time, a result of the cells becoming exhausted from being always "on."  A recent study from Stanford published in Science observed that giving cells a brief rest resets their cancer-killing ability.  The researchers generated CAR-T cells with a destabilizing domain incorporated into the protein responsible for the cells' cancer-fighting ability. The effect of the destabilizing domain, which disrupts the production of the protein, called a chimeric antigen receptor, or CAR, can be reversed by treatment with a small drug molecule.  Therefore, in the absence of the drug the levels of the CAR protein rapidly decrease giving the cell a “rest” and when the drug is reapplied to the cells, the CAR protein is produced turning the cells back “on”.  Exhausted cells that were allowed to rest for as few as four days were much better at attacking and killing cancer cells, and animals with tumors that were treated with the rested CAR-T cells lived significantly longer than those that received a control treatment. Turning off all the CAR-T cells in a patient could allow the remaining cancer to grow so future studies will be needed to determine how to selectively turn off a subset of CAR-T cells at a time. This type of fine tuning of cell functioning might prove more effective for cancer patients.