Tyrosine kinase inhibitor dasatinib as a drug switch for CAR-T cells


Introduction of CAR-T

T cells, also known as T lymphocytes, are a kind of human leukocytes, derived from bone marrow hematopoietic stem cells, mature in the thymus, and then migrate to human blood, lymph, and surrounding tissues and organs to play an immune function. Its function is equivalent to the “soldiers” in the human body and can resist and destroy “enemies” such as infections, tumors, foreign bodies and so on. In the laboratory, technicians use genetic engineering technology to activate T cells and install a positioning navigation device CAR (tumor chimeric antigen receptor) to transform T cells, an ordinary “soldier”, into a “super-soldier”, that is, CAR-T cells, which uses its “location and navigation device” CAR, to identify tumor cells in vivo and release a large number of effective factors through immunity, which can efficiently kill tumor cells and achieve the purpose of treating malignant tumors.

CAR-T therapy is chimeric antigen receptor T-cell immunotherapy is a new type of accurate targeted therapy for the treatment of tumors. In recent years, it has achieved good results in the treatment of clinical tumors through optimization and improvement. It is a very promising, accurate, rapid and efficient treatment. And it is possible to cure cancer with a new type of tumor immunotherapy. Unfortunately, this immunotherapy has its risks, and overactivation of CAR-T cells can sometimes cause serious and even fatal side effects. CAR-T cells are “living drugs” that require techniques that allow doctors (and patients) to maintain control of these T cells injected into patients. There are some ways to inhibit overactivated CAR-T cells, which can kill CAR-T cells, thus eliminating their toxic side effects and anti-tumor effects, but they are all used once and for all.

New Research of CAR-T

In a new study, Researchers from Wuerzburg University Hospital in Germany and Memorial Sloan-Catelyn Cancer Center in the United States have confirmed that the tyrosine kinase inhibitor dasatinib interferes with the lymphocyte-specific protein tyrosine kinase (LCK). Inhibit the phosphorylation of CD3 Zeta and T cell receptor-associated protein kinase 70 kDa (ZAP70) ζ chain, thus eliminating the signal transduction in the CAR structure containing CD28_CD3ζ or 4-1BB_CD3ζ activation modules. As a result, dasatinib induced a functional shutdown in CD8+ and CD4+ CAR-T cells, which took immediate effect and lasted for several days without affecting T cell activity. The results were published in the July 3, 2019 issue of the journal Science Translational Medicine under the title “The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells”.

The researchers found that treatment with dasatinib prevented the lytic activity, cytokine production and proliferation of CAR-T cells, both in vitro and in vivo. The dose of dasatinib could partially or completely inhibit the function of CAR-T cells after titration. After discontinuation of dasatinib, its inhibitory effect was reversed quickly and completely, and CAR-T cells regained their anti-tumor function. The beneficial pharmacodynamic properties of dasatinib can be used to control the activity of CAR-T cells in the “functional-on-off-on” sequence in real-time.

Conclusion

In the mouse model of cytokine release syndrome (CRS), these researchers demonstrated that short dasatinib treatment earlier after CAR-T cell infusion could protect some mice from fatal cytokine release syndrome. These data suggest that dasatinib can be introduced as a widely used drug on/off switch for CAR-T cells.

References

1. Mestermann, K., Giavridis, T., Weber, J., Rydzek, J., Frenz, S., Nerreter, T., … & Hudecek, M. (2019). The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Science translational medicine11(499), eaau5907.

2. Jackson, H. J., Rafiq, S., & Brentjens, R. J. (2016). Driving CAR T-cells forward. Nature reviews Clinical oncology13(6), 370.