Engineering optimal T-cells for the treatment of acute myeloid leukaemia

Morin, Theo 2024. Engineering optimal T-cells for the treatment of acute myeloid leukaemia. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Immunotherapy is the biggest breakthrough in cancer treatment for over 50 years. Killer Tcells engineered to express molecules called chimeric antigen receptors (CARs) have been successful for the treatment of acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and B-cell lymphoma. This ‘CAR-T’ therapy is now being delivered by the NHS for the treatment of B-cell acute lymphoblastic leukaemia (B-ALL) in nine centres across the UK. Unfortunately, CAR-T therapy is not successful for all refractory B-ALL patients due to antigen loss. CAR-T therapy is also not suitable for myeloid leukaemia because of the lack of safe targets on the tumour cell surface. The initial purpose of my project was to build ‘TCR-T’ cells and test how effectively they kill acute myeloid leukaemia (AML) cancer cell lines. A former PhD student in my laboratory, Dr Mateusz Legut, identified T-cell receptors (TCRs) that could recognise various leukaemia cell lines without the need for a specific human leukocyte antigen (HLA). These TCRs were selected from patients that have undergone successful immunotherapy for solid tumours and exhibited tumour regression. I aimed to first identify and dissect a selection of different ‘HLA-agnostic’ TCRs from metastatic melanoma TILs that could recognise AML cancer cell lines. These results are reported in Chapter 3. The second aim of my PhD was devoted to building a genetically engineered T-cell product developed to increase the co-stimulatory signalling for enhanced anticancer reactivity by developing a new concept termed ′side CARs′ (Chapter 4). Finally, the last aim of my PhD was to uncover the mechanism(s) governing HLA-agnostic TCR recognition of non-classical cancer-associated ligand(s). Ligand discovery was achieved using ex vivo generated mouse anti-human cancer antibody library raised against tumour cell surface proteins. Antibodies were screened to identify those that specifically blocked tumour cell recognition by TCRs of interest. Blocking antibodies were then used to immunoprecipitate the putative ligand which was then identified using mass spectrometry. The results in Chapter 5 begin to explore a new way of targeting many cancer types including AML without the requirement for HLA matching.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Funders:	Cancer Research Wales
Date of First Compliant Deposit:	22 August 2024
Last Modified:	22 Aug 2024 16:00
URI:	https://orca.cardiff.ac.uk/id/eprint/171541

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