Our spotlight showcases our innovative and pioneering research into cancer immunology.
Cutting off the supply lines for cancer, Dr Steve Lee and Professor Roy Bicknell:
For a tumour to grow it needs to induce new blood vessel formation to maintain a supply of nutrients and oxygen. However the blood vessels that form in tumour tissue are different from those that supply healthy tissues, both in their appearance and the genes that they express. Consequently, genes that are selectively turned on in the tumour vasculature are potential targets for therapy. We are targeting the product of one such gene, a protein known as CLEC14A. We have conducted extensive analyses on the expression of this gene in healthy and tumour tissues, and found it to be highly expressed in the vasculature of several solid human tumours. In contrast, in healthy tissues it is absent or expressed at very low levels.
To target CLEC14A on the tumour vasculature, we are using the body’s immune system. More specifically, we are taking T lymphocytes from the blood and genetically engineering them to stably express a Chimeric Antigen Receptor (CAR) that specifically binds CLEC14A. T cells expressing other types of CARs have been shown to be very potent killers, and are already proving highly effective at destroying some forms of leukaemia. Therefore by engineering T-cells to express a CAR specific for CLEC14A, we hope to selectively destroy the blood vessels that supply tumour tissues, and in so doing, inhibit tumour growth.
Having engineered T-cells to express our CAR, we have shown that when they encounter cells expressing the CLEC14A marker, not only do the T-cells proliferate and make cytokines such as interferon gamma, but they also kill the CLEC14A expressing target cell. Fortunately CLEC14A is well conserved between mouse and humans, and our CARs are able to respond to this protein in both species. Therefore as we seek to develop this approach as a therapy for cancer patients, we have explored both the safety and efficacy of our engineered CAR T-cells in mouse cancer models. These studies have shown that not only is the approach safe, but it is also effective, inhibiting tumour growth in 3 different mouse models of solid cancer.
We are currently working with the Cell and Gene Therapy Catapult (London, UK) and have set up a spin out company (Chimeric Therapeutics Ltd) to develop this towards Phase 1 clinical testing.