Scientific Publications

CAR T-cell therapy is considered a milestone in personalized cancer treatment. In this approach, a patient’s own immune cells are genetically modified to recognize and destroy tumor cells. While it has already shown impressive success in certain blood cancers, its effectiveness against solid tumors has so far been limited. An international research team led by Prof. Michel Sadelain, MD, PhD, of Columbia University in New York, in collaboration with Prof. Judith Feucht, MD, of University Hospital Tübingen, has now identified in animal models how this limitation might be overcome. Sadelain is regarded as one of the pioneers of CAR T-cell therapy, as his research has been instrumental in its development and clinical application.

NFIL3 – a key factor in preventing cell exhaustion

In a systematic screening, the researchers tested around 400 so-called transcription factors—proteins that regulate which genes in a cell are turned on or off. They found that the protein NFIL3 plays a major role in causing CAR T cells to become “exhausted” over time and lose their effectiveness. When NFIL3 is deactivated in these cells, they remain functional for longer, proliferate more effectively, and sustain stronger anti-tumor activity. This is achieved using CRISPR/Cas9 technology. Known as “gene editing scissors,” this method allows the NFIL3-encoding gene to be precisely cut and thereby inactivated. “Switching off NFIL3 could be a decisive step toward significantly improving the long-term potency of CAR T cells,” explains Prof. Feucht.

From basic research to patient application

In several mouse models, CAR T cells lacking NFIL3 were shown to fight tumors more effectively and extend survival. The study thus provides an important starting point for expanding treatment options for tumor types that have so far been difficult to treat. “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.

Research at the interface of science and clinical care

Prof. Judith Feucht uniquely combines research and clinical practice: 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 approach follows the “bench-to-bedside” principle—translating scientific findings directly into new therapies for young cancer patients. It will still take some time before these new insights reach clinical application, but the results provide reason for cautious optimism that this approach may also prove effective in humans.

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Wissenschaftlicher Ansprechpartner:
Prof. Judith Feucht, MD
Research Group Leader
Department of Pediatrics – Pediatric Hematology and Oncology
University Hospital Tübingen

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Originalpublikation:
Title of the original publication: Nayan Jain et al.: “Integrated chronic in vivo and in vitro screens uncover NFIL3 as a driver of T cell dysfunction.” Cancer Discovery.
DOI: 10.1158/2159-8290.CD-25-1524
https://doi.org/10.1158/2159-8290.CD-25-1524