Activating the body's own immune cells against cancer in the laboratory: This is the principle behind so-called CAR-T cell therapy, which is used very successfully for certain forms of cancer, such as acute lymphoblastic leukemia (ALL). However, the cancer sometimes recurs and some patients experience neurological symptoms. Scientists from the Faculty of Medicine at the University of Freiburg have now found a way to increase the effectiveness of CAR-T cell therapy in animal models and patient samples by inhibiting the signalling molecule TAK1, while at the same time reducing inflammatory reactions in the brain. The study was published on May 13, 2024, in the online journal Nature Cancer. Further studies must now clarify whether the approach is also safe and effective in humans.
Making immunotherapy for leukemia safer and more effective
Freiburg researchers have found a way to enhance the effect of cell-based CAR T-cell therapy in leukemia and reduce side effects
Study leader Prof. Dr. Robert Zeiser (left) and first author Dr. Janaki Manoja Vinnakota (right). Image: Britt Schilling
“The treatment approach we have developed could be an important step towards helping many more cancer patients with CAR-T cell therapies,” says Prof. Dr. Robert Zeiser, Head of the Department of Tumor Immunology and Immune Regulation at the Department of Internal Medicine I at the Freiburg University Medical Center.
Side effects clarified at the molecular level
Together with Prof. Dr. Marco Prinz, Medical Director of the Institute of Neuropathology at the Freiburg University Medical Center, Zeiser was able to identify the cell type and the specific signalling pathway responsible for the excessive immune response following CAR-T cell therapy in ALL. The research teams led by Zeiser and Prinz showed that the signalling molecule TAK1 is involved in the activation of immune cells in the brain, known as microglia, as part of the inflammatory response following CAR-T cell therapy.
New treatment approach developed
By inhibiting TAK1, the Freiburg researchers were able to stop the undesirable effects, namely the growth and inflammatory reactions in the brain. “In the next step, we want to test the safety and efficacy of this approach in patients,” says Zeiser.
The activation of microglia in inflammation is being investigated as part of the Collaborative Research Center SFB/TRR 156 “NeuroMAC” (spokesperson: Prinz). The combination of immunotherapy with the inhibition of cancer-promoting signals is a concept that is being investigated as part of the SFB1479 “OncoEscape” (spokesperson: Zeiser). Zeiser and Prinz are also investigating the principles of signal transduction as part of the Cluster of Excellence Centre for Integrative Biological Signalling Studies (CIBSS) at the University of Freiburg.
Original publication
Vinnakota, J.M., Biavasco, F., Schwabenland, M. et al. (2024). Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome. In: Nat Cancer. DOI: 10.1038/s43018-024-00764-7
Original press release by the University Medical Center Freiburg (in German)