The risk with introducing manipulated T-
cell is unforeseen adverse events. During the development of
chimeric antigen receptor (CAR) T-
cell therapies almost all
clinical trial has shown some adverse events
ranging from
cytokine mediated toxicities to
tissue damage and death. By the present invention, we aim to induce multiple
layers of safety checkpoints. As a last resort we will be able to induce suicide in all cells which we have introduced to the body. Here we describe the scientific background to the parts of our suicide switch and the details regarding the proteins which are included. Safety switches are being tested on CAR-T cells, but they have a few drawbacks. Due to the limited space on the CAR vector, there is only room for one
gene switch. Presently the results show they induce
apoptosis in around 70-90% of cells, while the desired target is for all cells to be removed from the tissue. By utilising the space available on a synthetic
chromosome, we can include multiple genes under Tet operons which allow us to turn multiple genes on / off. Life or death of a
cell depends on the balance of the pro and anti-apoptotic proteins. The scale is always shifting a bit back and forth but only when tipped completely over the apoptotic
cascade is initiated. By
fine tuning the balance we aim to ensure that the hSync carrying cells have a survival
advantage in the tumour in the absence of inducing agent. On the other hand, the moment that agent is administrated the cells will undergo
apoptosis and express “find me” and “eat me” markers making sure they are removed without risk of
tissue damage. The present invention encompasses compositions and methods for use in cellular
gene therapeutics using a modular approach to genetically engineer cells to carry a synthetic
chromosome having a regulatable
system including one or more safety switches.