Generating and characterising chimeric antigen receptors to target the tumour vasculature

Cawkwell, Lewis Blair (2018). Generating and characterising chimeric antigen receptors to target the tumour vasculature. University of Birmingham. Ph.D.

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Abstract

Tumour associated endothelial cells have been found to express markers not normally found within the mature, stable, adult vasculature network. These markers, termed tumour endothelial markers (TEMs) are potential targets for chimeric antigen receptor (CAR) T cell therapy. This project attempts to generate and characterise CARs against the novel TEMs: ROBO4, ELTD1, GRIND2 and MCAM.

In the first part of the project, ROBO4-specific CARs that signal through CD3ζ and CD28 signalling domains were characterised. ROBO4 CARs specifically retarget T cells to mouse and human ROBO4 in multiple in vitro assays of T cell function. ROBO4 CAR T cells also showed a slight but insignificant reduction in tumour growth compared to control CAR T cells. However, ROBO4 CAR T cells caused toxicity at high doses and whole body cryoimaging showed that ROBO4 CAR T cells accumulated in the lung and liver of healthy mice.

In the second part of the project, the ETH2-GOLD phage display library was used to recover novel antibodies with the aim of generating CARs. However, the generated ELTD1 CAR was non-functional in T cells and significant problems occurred while searching for antibodies to GRIN2D and MCAM.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):