Researchers have pinpointed a single protein that may be one of the biggest obstacles holding CAR-T cell therapy back, and shown that switching it off makes the cells dramatically more durable.
CAR-T therapy works by genetically modifying a patient's own immune cells to recognize and destroy tumors. It has produced striking successes in certain blood cancers, but against solid tumors its results have been limited, largely because the cells become "exhausted" and lose their fighting power over time.
An international team led by Michel Sadelain at Columbia University, working with Judith Feucht at University Hospital Tübingen, screened roughly 400 transcription factors, the proteins that switch genes on and off, to find what drives that exhaustion. One name rose to the top: NFIL3.
Using CRISPR/Cas9 gene editing to disable the gene that produces NFIL3, the researchers found the modified CAR-T cells stayed active longer, multiplied more efficiently, and maintained stronger anti-tumor effects across several mouse models. Cells lacking the protein controlled tumors better and extended survival.
The work is preclinical, demonstrated in animals rather than patients, but it suggests a concrete path toward making CAR-T effective against the solid tumors that have so far resisted it.
“"Switching off NFIL3 could be a decisive step toward significantly improving the long-term potency of CAR T cells."”Judith Feucht · Professor · University Hospital Tübingen