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Chimeric Antigen Receptor (CAR) T-cell Immunotherapy for MUC1-positive Breast Cancer

Student thesis: Doctoral ThesisDoctor of Philosophy

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.
Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date2018

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