Exploring the therapeutic potential of CAR-engineered T-cells targeting endothelial markers on tumour and inflamed vasculature

Petrovic, Kristina (2018). Exploring the therapeutic potential of CAR-engineered T-cells targeting endothelial markers on tumour and inflamed vasculature. University of Birmingham. Ph.D.

Preview

Petrovic18PhD.pdf
PDF - Accepted Version
Download (24MB)

Abstract

T-cells engineered to target tumour antigens through surface-expressed chimeric antigen receptors (CARs) are highly effective in treating some leukaemias. The challenge is to extend this success to solid tumours. Tumour endothelial marker 8 (TEM8) is a conserved transmembrane protein overexpressed on the vasculature of many solid tumours but low or undetectable on healthy tissues, making it a potential CAR T -cell target. This thesis explores the safety and therapeutic efficacy of this approach by generating five human TEM8-specific CARs, expressing them in T-lymphocytes, and characterising their functional responses to TEM8 in vitro. Four of the five CARs showed unexpected reactivity to control cells, and in mouse studies some of these proved toxic while most were selectively lost from the circulation, an effect that was TEM8-dependent. Only one CAR selectively responded to target cells overexpressing human TEM8 in vitro but was unable to recognise mouse TEM8, so further in vivo studies were not possible. These results highlight the sensitivity and potency of CAR -engineered T -cells and demonstrate the need for additional safety measures if targeting TEM8. The thesis also demonstrates that another TEM, CLEC14A, is overexpressed in some inflammatory liver diseases, and identifies a suitable mouse model for exploring the therapeutic potential ofCLEC14A-specific CAR-expressing regulatory T-cells.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):