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Title: Chimeric antigen receptor (CAR) T-cell immunotherapy for MUC1-positive breast cancer
Author: Gavriil, Artemis
ISNI:       0000 0004 7223 5300
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Cancer immunotherapy using chimeric antigen receptor (CAR) T-cells has shown exceptional promise in the treatment of patients with refractory B-cell malignancy. In this approach, patient-derived peripheral blood T-cells are engineered to express a cell surface receptor, which confers specificity for a tumour-associated (TA) antigen. Mucin-1 (MUC1) is a large transmembrane glycoprotein that is overexpressed in 90% of breast cancers. A further important characteristic of this mucin is the fact that it is under-glycosylated in cancer cells. This holds the potential for CAR T-cell mediated targeting of MUC1 epitopes in tumour-cells which are not exposed in normal cells. Antibodies such as TAB004 and HMFG2 are considered to bind preferentially to TA-MUC1. The aim of this PhD project was the development of a CAR Tcell approach for MUC1-positive breast cancer. Herein, the anti-tumour potential of a novel 2nd generation MUC1-specific CAR, named TAB28z, has been investigated. The binding domain of this CAR is derived from the TAB004 anti-MUC1 antibody. TAB28z is being compared with two other previously developed MUC1-specific CARs, H28z and HDF28z, both of which are derived from the HMFG2 antibody. TAB28z CAR T-cells demonstrated significant anti-tumour activity against MUC1-positive breast cancer cell lines in the in vitro setting. Nevertheless, it became apparent throughout this project that MUC1 expressed on activated T-cells is detected by both HMFG2-based and TAB004-based CAR T-cells during the T-cell expansion period. This background recognition resulted in tonic signalling by CARs, which was accompanied by constitutive production of IFN-γ, CAR T-cell enrichment, reduced T-cell expansion and a trend towards upregulation of T-cell activation and exhaustion markers. Despite these observations, the activity of the three MUC1-specific signalling CARs was investigated in two different breast cancer xenograft models. No significant anti-tumour responses were observed in either of the two models, which could possibly be attributed to the effects of tonic signalling.
Supervisor: Papa, Sophie Elinor ; Maher, John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available