Team:Freiburg/HP/Gold Integrated
Integrated Human Practice
Kill Switch for Activated T cells
To improve the safety of the Cartel cells, a kill switch can be implemented in order to specifically eliminate CAR T cells which produced side effects. This switch is controlled by a drug, that is not damaging unmodified cells An approach frequently used in clinical studies of transplanted lymphocytes is the virostatic drug ganciclovir (GVC) and its effector, the thymidine kinase commonly expressed by cells infected with herpesviruses like the herpes simplex virus 1 [HSV1].
Mechanism
Ganciclovir is commonly used as medication against human cytomegalovirus like Herpes Simplex Virus 1 as it acts as a virostatic. It has a high affinity to viral kinases, like the thymidine kinase expressed by infected cells. These kinases initiate the metabolization of Ganciclovir into a nucleoside analogue, which subsequently is integrated into the DNA by the DNA polymerase, resulting into disruption of DNA replication of proliferating cells. It is assumed, that the DNA instability leads to activation of caspase-9, which triggers processes associated with apoptosis.
Waseem Quasim, et al. (2017): Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Science Translational Medicine, 25 Jan, Vol. 9, Issue 374.
