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Researchers at the Medical Center - University of Freiburg are developing innovative approaches to minimize the risk of severe side effects in CAR-T cell therapy, opening up new avenues for safer cancer treatments

A recent study by the Institute of Transfusional Medicine and Genetherapy and the Center for Chronic Immunodeficiency (CCI) at the Medical Center - University of Freiburg shows promising approaches to reducing side effects of CAR-T cell therapy, especially cytokine release syndrome (CRS). In mild cases, CRS can manifest itself as flu-like symptoms such as fever, nausea or chills. In severe cases, however, it can result in life-threatening reactions. The research, published on November 6, 2023 in the journal Cells, highlights the importance of these discoveries for patients with blood cancers, where previous treatment methods have been associated with significant side effects.

"These new models offer us a unique opportunity to better understand and target the mechanisms of CRS without compromising the efficacy of CAR-T cells," explains study leader Prof. Dr. Toni Cathomen, Head of the Institute of Transfusional Medicine and Genetherapy at the Medical Center - University of Freiburg and member of the Faculty of Medicine - University of Freiburg.

Innovative research methods for safer treatments

In this study, the researchers developed two simplified laboratory models to understand how a dangerous overreaction of the immune system, known as cytokine release syndrome (CRS), occurs during cancer immunotherapy with CAR-T cells. These models mimic the reactions of three cell types: Cancer cells, CAR-T cells and certain immune cells in the body called monocytes. When the CAR-T cells encounter cancer cells, they stimulate the monocytes to produce an inflammatory substance (IL-6), which is important for triggering CRS. "We were able to show that certain interventions, such as blocking specific molecules or changing their genes with the CRISPR gene scissors, reduce the production of this inflammatory substance. This offers new opportunities to reduce the side effects of CAR-T cell therapies," says study leader Cathomen.

A major advantage of the new cell-based models over previous approaches is their simplicity and efficiency. While previous models, such as animal models, were labor-intensive and only partially suitable for screening procedures, the new in vitro models enable a faster and more precise investigation of the interactions between CAR-T cells and monocytes. "These models make it possible to precisely observe how genetic changes in the CAR-T cells influence the cytokine release syndrome without having to carry out laborious animal experiments," says Cathomen.