Project description
Synthetic CAR T platform for effective cancer treatment
CAR T cell therapy shows promise as a cancer treatment, involving the genetic modification of T cells to target cancer cells. However, this therapy can lead to severe side effects and offers limited effectiveness. Researchers are seeking to enhance CAR T cell function, but existing off-the-shelf approaches with complete control over CAR T effector function incur high manufacturing costs. The ERC-funded SynCAR-Ts project aims to create a universal synthetic CAR T cell platform. This platform features an adaptable antigen receptor regulated by synthetic, functionalised targeting ligands. Leveraging highly reactive aryl nitrenium ions, the project will modify proteins, deliver drugs, and develop therapeutics. The goal is to broaden the CAR T targeting spectrum to encompass solid tumours and beyond.
Objective
Chimeric antigen receptor (CAR) T cell therapy is a promising approach for cancer treatment with remarkable clinical outcomes. CAR T therapy involves the isolation of patients T cells that are genetically modified with an engineered antigen receptor to attack cancer cells.
Despite the great promise, the rapid activation and proliferation of CAR T cells can lead to serious side effects. In addition, CAR T therapy is challenged by limited effectiveness, difficulties in infiltrating solid tumors, targeting of healthy cells, cell exhaustion and an expensive, lengthy and personalized manufacturing process. Over the past years, researchers have explored many strategies to improve and control CAR T cell function and to develop more universal CAR T cell platforms. Yet, an off-the-shelf approach that allows full control of CAR T effector function, that is flexible in use and can be obtained at low manufacturing costs, is currently not available.
To address above challenges, I will develop a highly innovative, universal synthetic CAR (SynCAR) T cell platform where the antigen receptor is easily adaptable by using synthetic, functionalized targeting ligands to control T cell effector function in space and time.
At the basis of this proposal lies the use of highly reactive and activatable aryl nitrenium ions for protein modification, drug delivery and as novel class of therapeutics. I will 1) tune nitrenium ion reactivity for bioconjugation and drug activation 2) use enzyme-activatable nitrenium ion precursors for synthetically modified antigen receptors, 3) develop novel nitrenium ion-based prodrug strategies to improve CAR T efficiency and 4) use innovative bioorthogonal chemistry to control CAR T activity in time and space.
In this work, I will develop beyond the state-of-the-art chemical biology methods and molecular targeting tools to control, potentiate, and tune T cell activity with the ultimate goal to broaden the CAR T targeting landscape to solid tumors and beyond.
Fields of science
Not validated
Not validated
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
2311 EZ Leiden
Netherlands