Wawrzyniecka, Patrycja Anna; (2023) IL13ra2-Targeted CAR T Cell Therapy for High-Grade Gliomas. Doctoral thesis (Ph.D), UCL (University College London).

Text Patrycja Wawrzyniecka - PhD thesis FINAL.pdf - Accepted Version Access restricted to UCL open access staff until 1 September 2025. Download (22MB)

Abstract

IL13ra2 is a type I transmembrane protein. It is one of two receptors for IL13, alongside IL13r1. Unlike IL13r1, it is not ubiquitously expressed in the human body. However, it is expressed by many solid tumours, including high-grade gliomas. Being expressed on the cell surface of cancerous cells but not healthy tissues make IL13ra2 a suitable target for Chimeric Antigen Receptor (CAR) T cell therapy. This thesis describes the generation of an αIL13ra2 library and the panning process to select individual binders. The library was tested by Next Generation Sequencing (NGS) to elucidate the possibility of selecting a large and diverse pool of binders with out the necessity for manual picking. The isolated binders, both from manual picking and NGS-derived, were tested in-depth and characterised to test their specificity and binding kinetics. The specific binders were engineered into a second-generation CAR format and tested for their anti-tumoural activity, proliferation and cytokine secretion in a number of in vitro assays. Once the best performing binder was found, the CAR was further engineered by introducing immunosuppressive tumour microenvironment tackling modules. These were further tested in vitro and in vivo. An armoured CAR was developed that was shown to be efficacious both in vitro and in vivo. It was considered to be a great candidate for future use in clinical trial(s) targeting high-grade gliomas. To ensure the safety of using αIL13ra2 CAR T cells in a clinical trial, a tissue cross reactivity study was conducted to ensure the chosen antibody does not nonspecifically bind outside the tumour site. Finally, a novel strategy was proposed to disrupt the tumour microenvironment and prevent antigen-negative tumour escape which frequently hinders effectiveness of CAR T cell therapy. This was done by combining an expression of an enzyme capable of hydrolysing a non-cytotoxic, systemically administered prodrug into a cytotoxic drug at the tumour site by the CAR T cell.

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