Bailey, Katharine Elizabeth;
(2019)
CD20 as a prognostic biomarker and as a potential therapeutic target of oncolytic measles virus in adult acute lymphoblastic leukaemia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Adult acute lymphoblastic leukaemia (ALL) is an aggressive haematological malignancy with a poor outcome for 50% of patients. CD20 is an important target antigen in ALL. I have examined the role of CD20 as a biomarker in ALL and investigated whether an oncolytic measles virus (MV) targeted to CD20 is therapeutically relevant. In Chapter 3, I analysed CD20 expression in primary specimens from the UKALL14 trial. Increasing CD20 expression ‐ whether measured by the percentage of positive ALL cells or as CD20 antigen density ‐ conferred inferior survival. I developed a RT‐qPCR assay to quantify the gene expression of CD20 for use in specimens without stored cells. This correlated well with the flow cytometry data with a similar relationship to outcome. ALL cells are known to be sensitive to MV oncolysis. Chapter 4 of my thesis investigated the therapeutic potential of a MV genetically modified to target entry via CD20. MVHCD20 was more effective than the native MV at killing CD20 positive cells in vitro. A MV ‘blinded’ to the native MV receptors by ablation of the residues necessary for receptor‐binding also demonstrated efficacy suggesting it would have therapeutic efficacy whilst avoiding offtarget effects. In Chapter 5 I investigated the underlying mechanism of the MV oncolysis previously demonstrated. Neutrophils are effector cells in MV‐oncolysis but not by antibody dependent cellular cytotoxicity, as previously shown by my lab, so I explored their role in antibody‐mediated phagocytosis after CD20 targeted MV infection of ALL cells. I demonstrated that true phagocytosis was a rare event. However, neutrophils demonstrated an antibody‐dependent cellular process called ‘trogocytosis’. Trogocytosis did not result in target cell death, however it appeared to increase neutrophil activation, which suggests that activated neutrophils may orchestrate additional immune responses following MV oncolysis.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | CD20 as a prognostic biomarker and as a potential therapeutic target of oncolytic measles virus in adult acute lymphoblastic leukaemia |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10080017 |
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