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Development of novel B7-H3 targeted CAR therapy for neuroblastoma

Birley, Kathleen; (2021) Development of novel B7-H3 targeted CAR therapy for neuroblastoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite improvements in treatment of childhood cancer, many childhood solid tumours, including high risk neuroblastoma, continue to have poor outcomes with high levels of mortality and morbidity associated with current treatment regimens. B7-H3 is a protein highly expressed in most types of cancer but with a restricted expression on healthy cells. It’s mechanism of action is poorly understood but it is believed have a role in T cell inhibition and to have some non-immunological effects on tumorigenesis. The expression pattern and potential for checkpoint inhibition make B7-H3 an exciting novel target for immunotherapy. Seventeen unique anti-B7-H3 single chain variable fragments (scFvs) were identified from an existing phage display library. These were tested against recombinant and cell-bound B7-H3. Five scFv were taken forward into Chimeric Antigen Receptor (CAR) T cell format and of these, the scFv TE9 showed superior cytokine production and was selected as the lead. TE9 was compared with two other anti-B7-H3 scFvs recently described in the literature and showed equivalent anti-cancer activity in vitro. TE9 was tested in vivo in a neuroblastoma xenograft model where it brought about prolonged survival compared with an anti-GD2 CAR recently in clinical trial. B7-H3 has been successfully targeted with TE9 CAR T cells and this antigen/treatment combination was superior to targeting GD2 with an anti-GD2 CAR. TE9 CAR T cells represent a promising novel therapeutic for paediatric solid tumours including neuroblastoma.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of novel B7-H3 targeted CAR therapy for neuroblastoma
Event: University College London
Language: English
Additional information: Copyright © The Author 2021. 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 > 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 > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10132979
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