Template:Freiburg/Example
Example
Cancer is one of the most important challenges medical research has to overcome. Cancer tissue originates from healthy cells mainly through genetic changes which dysregulate cellular processes especially growth and metabolism. For this reason the treatment is challenging, as each cancer is different and keeps changing, making it difficult to find the best therapy. Common approaches such as radiation or chemotherapy can lead to severe short and long-term side-effects. To avoid these, the focus of cancer therapy development changed to immunotherapy. Here the ability of the immune system to fight cancer cells is being improved. During the last years, special attention in immunotherapy has been gathered by chimeric antigen receptor (CAR) immunotherapy. (Hollie J. J. et al. 2016; Fesnak A. et al. 2016).
In CAR immunotherapy, T cells are extracted from patient blood and genetically modified to express CAR constitutively. T cells are cells of the immune system which are derived from the thymus and have various functions in fighting pathogens and cancer. Afterwards, the modified cells are re-injected into the patient where they exhibit an enhanced ability to target cancer cells through the CAR. The CAR is a synthetic receptor composed of signaling subunits of a T-cell receptor and the variable region of an antibody thereby combining the function of antigen binding with T cell activation. As for now, CAR therapies are in clinical trials for B cell lymphomas and were recently approved by the FDA for therapeutic use (Clinical Study CCTL019B2202).
One challenge with CAR immunotherapy is the emergence of a major side effect, the Graft-Versus-Host-Disease (GVHD). The antigen recognized by the CAR is not exclusive for tumor cells. Thus healthy cells presenting the same antigen can be targeted by CAR T cells leading to the damage of healthy tissue. To overcome this very issue, we came up with the idea that a locally restricted expression of the CAR would prevent off-target effects. For our project, we designed a genetic logical AND-gate which is activated by the tumor microenvironment of solid tumors. Regulated by the AND-gate CAR is only expressed if the T cells are within tumor tissue. This local restriction of CAR expression should decrease the risk of off-target effects
Our approach to improve CAR immunotherapy is based on genetic engineering of T cells to express CAR only in specific tumor microenvironment. This would allow to treat cancer patients without changing immunogenicity of the modified T cells, neglect conventional cancer treatments and also minimize the risk of severe side-effects.
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.
