Wisidagamage Don, Nisansala;
(2023)
Investigation of T cell based therapeutic strategies to target Acute Myeloid Leukaemia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Acute myeloid leukaemia (AML) is a highly heterogeneous clonal disease of the myeloid line of blood cells. It is characterized by an abnormal accumulation of immature leukemic cells in the bone marrow and blood, thus, interfering with normal haematopoiesis and leading to bone marrow insufficiency. One of the main limitations of current strategies is the potential on-target off-tumour toxicity due to the expression profile of currently targeted tumour antigens. The aim of this work was exploring different approaches to overcome this limitation. We investigated the antitumour activity of second-generation CAR targeting CD33 and a novel antigen with a more restricted expression profile, B7-H3. We found that TE9-CD8-28ζ CAR T cells targeting B7H3, were able to drive a potent antitumor response in an antigen-dependent manner, in vitro. Importantly we also demonstrated lack of hematopoietic toxicity mediated by TE9-CD8-28ζ CAR T cells, addressing one of the main limitations of current strategies targeting AML. Another approach consisting of αβ T cells engineered to co-express a γδTCR and an B7-H3-targeting chimeric costimulatory receptor (TE9-CCR), was also explored. This system aims to drive potent anti-tumour responses through co-stimulation as well as avoid on target on tumour toxicity by separating signal 1 (TCR) and signal 2 (CCR). We demonstrated that γδ TCR-TE9-28 transduced αβ T cells were able to mount a robust anti-tumour response in vitro in an antigen-dependent manner, with full activation only when the CCR engaged the cognate antigen. In addition, preliminary evidence also showed the potential of γδ TCR-TE9-28 transduced αβ T cells to avoid on target of tumour toxicity in vitro.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigation of T cell based therapeutic strategies to target Acute Myeloid Leukaemia |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > ICH - Education Administration Team |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10172074 |
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