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Genome editing approaches for development of pan-population immunotherapies

Legut, Mateusz 2017. Genome editing approaches for development of pan-population immunotherapies. PhD Thesis, Cardiff Univeristy.
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Abstract

Background - T-cell based immunotherapy is the greatest recent breakthrough in cancer treatment, and can induce complete lasting remission. T-cells are capable of responding to a vast diversity of antigens via their hypervariable T-cell receptor (TCR). However, current immunotherapies rely on αβ T-cells which are restricted to person-specific Human Leukocyte Antigen (HLA) molecules presenting peptides from cancer-specific antigens. Thus, a given αβ TCR therapy is applicable only to a minority of patients. In contrast, γδ T-cells, and some αβ T-cells, recognise diverse cancer types regardless of the HLA type. The aims of my thesis were to investigate the potential of using non-HLA restricted T-cells and their receptors for cancer immunotherapy, and to develop tools to facilitate the study of non-HLA restricted T-cells for cancer treatment. Results – Initially, I developed a CRISPR/Cas9 method for generation of superior TCR transduced cells, in terms of their anticancer reactivity and antigen sensitivity, in comparison to TCR transduced cells generated by current clinical methodologies. Using this TCR replacement method I demonstrated that the anticancer reactivity of broadly cancer-reactive γδ T-cells derived from a variety of clinically relevant sources is dependent on their TCRs. I also used CRISPR/Cas9 genome editing to generate a panel of cancer cell lines deficient in known ligands of non-HLA restricted T-cells that can be used for initial dissection of their anticancer reactivity. Using this approach, I demonstrated that one of non-HLA restricted T-cell clones I procured recognised targets via CD1a. Finally, I developed a whole genome CRISPR/Cas9 pipeline for discovery of ligands and pathways essential for cancer cell recognition by non-HLA restricted T-cells. Conclusions – My research demonstrated that TCRs from broadly cancer-reactive T-cells can be used to re-direct primary T-cells to many cancer types regardless of their HLA type, paving the way for pan-population immunotherapy. The discovery of non-HLA ligands for broadly cancer-reactive T-cells can be achieved using whole genome and targeted CRISPR/Cas9 gene editing technology.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 2 November 2017
Last Modified: 02 Nov 2017 10:31
URI: http://orca-mwe.cf.ac.uk/id/eprint/106039

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