Investigating fine tuning of dual chimeric antigen receptors through library screen and investigation of drug induced receptor degradation

Chimeric antigen receptor engineered T cell (CAR-T) technologies have paved the way towards new and innovative treatments for cancer based on redirecting the immune system towards recognition of cancer specific cell surface target antigens, and subsequent specific T cell activation. A limitation of current approaches is that T cells can become exhausted or dysfunctional at the tumour site because of the need for continued and sustained T cell activation for tumour elimination. One approach for sustaining activation has been to split T cell signalling between two separate receptors, recognising the same or different antigens, and each providing distinctive forms of primary stimulation of co-stimulation: this design is described as dual CAR. One particular approach that enhances sensitivity to low antigen target density is use of a chimeric costimulatory receptor (CCR) that provides very effective 41BB costimulation when the 41BB is placed adjacent to the cell membrane, and the CCR is co-expressed with conventional second-generation CAR.
As a method to control signalling and mitigate T cell exhaustion in conventional CAR-T cells, the host lab has devised and developed drug induced degradation of CAR-T cells whereby immunomodulatory (IMiD) drugs (thalidomide derivatives) induce T cell regulation. Fine-tuning of duration of CAR-T activity and intermittent rest is achieved through alternate drug scheduling and dosing.
In this PhD proposal the student will investigate different approaches to fine tune dual CARs both through the refinement of the T cell signaling domains and the respective receptors, and through intermittent degradation of the dual components through grafting of 62 amino acid degron sequences onto one or both receptor molecules.