British Society for Haematology. Listening. Learning. Leading British Society for Haematology. Listening. Learning. Leading
11 July 2019

Researchers have shown that an existing leukaemia drug is able to temporarily ‘pause’ the activity of CAR T cell therapy in mice – a finding which could pave the way for better management of the treatment’s side effects.

The research, published in Science Translational Medicine, found that the paused cells lost none of their potency, and quickly resumed killing cancer cells when they were reactivated.

Although CAR T cell therapy has revolutionised the treatment of blood cancer, it can also cause life-threatening side effects, such as cytokine release syndrome (CRS).

The researchers found that administering dasatinib to mice soon after CAR T cell infusion prevented the onset of fatal CRS in 70% of the rodents, while only 25% of untreated mice survived CRS.

These findings indicate that dasatinib could potentially be used an emergency drug to quickly snuff out CRS and other adverse effects in patients receiving CAR T cell infusions.

This latest discovery by scientists from Memorial Sloan Kettering Cancer Center in New York, USA, and University Hospital Würzburg, Germany, means that patients could be better protected against these side effects.

Existing methods that have been developed to restrain the activity and toxicity of CAR T cells usually kill the cells, erasing their anti-cancer benefits.

However, Dr Katrin Mestermann and colleagues discovered that dasatinib puts CD4+ and CD8+ CAR T cells into a dormant state by interfering with the LCK enzyme, stopping the cells from proliferating or secreting inflammatory molecules.

Mestermann and her team found that dasatinib could immediately and completely halt the activity of CAR T cells for seven days – unlike dexamethasone, which is commonly used to control CAR T cell therapy.

Removing dasatinib rapidly restored CAR T cell activity, and the revived cells could induce cell death as effectively as untreated CAR T cells.


Source: Mestermann, K., Giavridis, T., Weber, J., Rydzek, J., Frenz, S., Nerreter, T., Mades, A., Sadelain, M., Einsele, H., Hudecek, M. (2019) “The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR-T cells”, Science Translational Medicine, available from doi: 10.1126/scitranslmed.aau5907

 

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