Engineered T cells have a habit that oncologists know well. They go in, they work, and then they quietly clock off. CAR T-cell therapy, in which cells taken from the patient are modified to recognise cancer, has produced remarkable results in some blood cancers. Against solid tumors it has done far less, and the fatigue of the cells is a large part of the reason.
A team from Columbia University and University Hospital Tübingen now says it has found one of the switches responsible. The protein is NFIL3, and when the researchers disabled it, the cells kept working.
A screen of roughly 400 candidates
The work was led by Michel Sadelain of Columbia, widely regarded as a pioneer of the therapy, together with Judith Feucht of Tübingen. Rather than guess, they tested around 400 transcription factors, proteins that act as dimmer switches for genes.
NFIL3 rose to the top as a driver of exhaustion, the gradual loss of function that sets in when T cells fight a tumor for too long. The team used CRISPR/Cas9 to cut out the gene that produces the protein. Cells without it stayed active longer, multiplied more efficiently and kept up a stronger attack on tumor tissue.
Across several mouse models, CAR T cells without NFIL3 held tumors in check better and lengthened survival. The finding appears in Cancer Discovery, under the title “Integrated chronic in vivo and in vitro screens uncover NFIL3 as a driver of T cell dysfunction.”
“Switching off NFIL3 could be a decisive step toward significantly improving the long-term potency of CAR T cells,” Feucht said. Celina May, co-first author and a member of Feucht’s group, put the aim plainly: “Our goal is to improve the effectiveness of CAR T cells in solid tumors as well.”
Mice, not patients
Every result so far comes from animal models. Further research will be needed before anyone tests the strategy in people, and the Tübingen press office described the outlook as reason for cautious optimism rather than anything firmer.
Feucht works at both ends of the pipeline. She does her research within iFIT, Germany’s only Cluster of Excellence in oncology, and she also treats children and adolescents in the pediatrics department at University Hospital Tübingen.
Sources
- A single protein may be holding back CAR T cancer therapy
- International Study identifies key protein in immune cell exhaustion in cancer immunotherapy
