Researchers from Columbia University and University Hospital Tübingen have discovered a protein that appears to play a major role in weakening CAR T cells over time. By disabling the protein, known as NFIL3, the scientists found that these engineered immune cells remained active longer and were better able to attack tumors. The findings, published in Cancer Discovery, could help improve CAR T-cell therapy, particularly against solid tumors that have proven difficult to treat.
CAR T-cell therapy is one of the most advanced forms of personalized cancer treatment. The approach involves collecting a patient's own immune cells, genetically modifying them to recognize cancer, and then returning them to the body to seek out and destroy tumor cells.
The therapy has produced remarkable results for some blood cancers. However, it has been far less successful against solid tumors. An international team led by Prof. Michel Sadelain, MD, PhD, of Columbia University, working with Prof. Judith Feucht, MD, of University Hospital Tübingen, set out to better understand why. Sadelain is widely recognized as one of the pioneers of CAR T-cell therapy and has played a key role in its development and clinical use.
To identify factors that limit CAR T-cell performance, the researchers conducted a large-scale analysis of roughly 400 transcription factors, proteins that control which genes are switched on or off inside cells.
Their investigation pointed to NFIL3 as a major contributor to CAR T-cell exhaustion, a process in which the cells gradually lose their ability to function effectively. When the researchers removed NFIL3, the CAR T cells stayed active for longer periods, multiplied more efficiently, and maintained stronger anti-tumor effects.
The team used CRISPR/Cas9 gene-editing technology to disable the gene responsible for producing NFIL3. Often described as genetic scissors, CRISPR allows scientists to precisely cut and modify DNA.
"Switching off NFIL3 could be a decisive step toward significantly improving the long-term potency of CAR T cells," explains Prof. Feucht.
The benefits of removing NFIL3 were demonstrated across several mouse models. CAR T cells lacking the protein were more effective at controlling tumors and helped extend survival.
The results suggest a possible path toward improving treatment for cancers that currently respond poorly to CAR T-cell therapy, particularly solid tumors.
"Our goal is to improve the effectiveness of CAR T cells in solid tumors as well," says Celina May, co-first author of the study and a member of Prof. Feucht's research group. "We expect this to open up new possibilities in the treatment of cancer patients," adds Feucht.
Prof. Feucht combines cancer research with hands-on clinical care. She conducts research within Germany's only Cluster of Excellence in oncology, iFIT (Image Guided and Functionally Instructed Tumor Therapies), while also treating children and adolescents at the Department of Pediatrics at University Hospital Tübingen.
Her work follows the "bench-to-bedside" approach, which focuses on translating scientific discoveries into treatments that can directly benefit patients.
Although additional research will be needed before this strategy can be tested and used in people, the findings provide encouraging evidence that targeting NFIL3 could strengthen CAR T-cell therapy and potentially expand its usefulness against a wider range of cancers.
