“Switching off NFIL3 could be a decisive step toward significantly improving the long-term potency of CAR T cells,” said Prof. Judith Feucht of University Hospital Tübingen. Her team, working with Columbia University, reported this week that a single protein appears to wear these engineered immune cells down.
The protein is NFIL3. In mice, CAR T cells that lacked it stayed active longer, multiplied more efficiently and kept up stronger attacks on tumors. The findings appeared in the journal Cancer Discovery.
CAR T therapy starts with a patient’s own immune cells. Doctors collect them, modify them genetically so they recognize cancer, and return them to the body to hunt tumor cells. Some blood cancers have responded remarkably well. Solid tumors have not.
An international team led by Prof. Michel Sadelain of Columbia set out to find out why. Sadelain is regarded as one of the pioneers of CAR T therapy and helped develop its clinical use. Working with Feucht, he and the group screened roughly 400 transcription factors, the proteins that decide which genes are switched on or off inside a cell. NFIL3 stood out as a major contributor to exhaustion, the gradual loss of a T cell’s ability to do its job.
Cutting the gene
To test the idea, the researchers used CRISPR/Cas9, often described as genetic scissors, to disable the gene that produces NFIL3. The edited cells did better across several mouse models. They controlled tumors more effectively, and the animals that received them lived longer.
“Our goal is to improve the effectiveness of CAR T cells in solid tumors as well,” said Celina May, co-first author of the study and a member of Feucht’s research group. Feucht added: “We expect this to open up new possibilities in the treatment of cancer patients.”
Feucht splits her time between the lab and the clinic. She does research within iFIT, Germany’s only Cluster of Excellence in oncology, and treats children and adolescents in the pediatrics department at the Tübingen hospital. Her work follows a bench-to-bedside approach, meaning discoveries are meant to reach patients.
That step has not happened here. More research is needed before the strategy can be tested in people, and the work so far is limited to animal models.
