Alam, Farah Masood;
(2025)
The effects of radiation on CAR-T cell functionality against neuroblastoma, within the context of an intact immune system.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Despite the success of CAR-T cells in the treatment of haematological malignancies, similar success has not been achieved in solid tumours, such as neuroblastoma, where high-risk disease yields poor survival outcomes. The immunosuppressive tumour microenvironment in neuroblastoma impedes CAR-T cell trafficking and persistence for effective anti-tumour response. Radiotherapy, a standard cancer treatment, can potentially enhance CAR-T cell therapy against neuroblastoma via immune-mediated effects. These effects depend on a regulated form of cell death (immunogenic cell death), which requires an intact immune system for an effective anti-tumour response. This study aimed to assess the effect of radiation on CAR-T cell activity against neuroblastoma within an intact immune system. An in vitro radiosensitivity screen of TH-MYCN transgenic mouse models of high-risk neuroblastoma showed varying radiosensitivity based on the expression of known immunogenic cell death markers and cell viability, making them suitable models for investigating radiotherapy and CAR-T cell combinations. The anti-B7-H3 ScFv 376.96, which targets B7-H3 expressing neuroblastoma and cross-reacts with human and mouse B7-H3, was evaluated as a CAR candidate. While optimisations improved initial CAR expression, lack of sustained expression and functionality made the 376.96 CAR unsuitable for this study. An alternative CAR, HuK666, targeting GD2, showed stable expression and sustained functionality in vitro. Irradiation of GD2+ targets with 2Gy or 8Gy did not enhance CAR-T cell functionality compared to controls but induced T-cell subset changes within the CAR population. These results suggest that radiation affects HuK666 CAR functionality. Further studies are needed to optimise the radiation regimen to determine whether this improves CAR-T cell treatment efficacy against neuroblastoma.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The effects of radiation on CAR-T cell functionality against neuroblastoma, within the context of an intact immune system |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10216572 |
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