Synthetically lethal adoptive T cell therapy

Background

Chimeric antigen receptors (CARs) endow T cells with the ability to respond to antigens in an MHC-independent manner. CAR T cell therapy has proven effective in the treatment of haematological malignancies and autoimmune disease; however, their efficacy is limited in solid tumour setting often because of the lack of targetable tumour-specific antigens, with on-target, off-tumour targeting being a leading cause of CAR T cell toxicity. 

Objective

The aim of this project is to develop pairs of chimeric antigen receptor (CARs) targeting different solid tumour antigens that can be combined to create AND gates to address the problem of on-target, off-tumour toxicity and increase CAR T cell efficacy. We propose to develop novel split CARs fused to either apoptotic factors or cytotoxic proteins that will be delivered in pairs to tumour cells to induce cell death. By splitting the apoptotic factors or cytotoxic proteins into two or more CARs, it should be possible to construct AND gates to ensure that only tumour cells are targeted by CAR T cells and that healthy tissue is spared.

This project is suited to PhD students looking to apply their knowledge to the development of CAR T cell therapies with the aim of translating them to the clinic. 

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