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The Role of Metabolites and Bioreactor Operating Conditions on T Cell Manufacturing

Amini, Arman; (2021) The Role of Metabolites and Bioreactor Operating Conditions on T Cell Manufacturing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a treatment for haematological malignancies with currently two products approved by the FDA in the USA and EMA in Europe (Kymriah™ and Yescarta™). Recent clinical studies demonstrated that the presence of less differentiated and long-lasting subsets such, as T Central Memory (TCM) cells in the CAR-T products is required to improve their clinical efficacy. Most manufacturing protocols use media containing high glucose concentration when expanding CAR-T cells ex vivo. Effector subsets primarily utilise glucose and glycolysis as a primary metabolic pathway, therefore, the hypothesis was that culturing T cells in a glucose deprived environment would limit T cell differentiation and effector subsets growth, producing TCM enriched products. It was demonstrated that a 2-stage feeding strategy, where CAR-T cells are activated and transduced in the presence of glucose and fed with a glucose-free medium during the expansion phase, would consistently produce a TCM enriched CAR-T product. Improved in vitro functionality and proliferation capability was demonstrated using TCM enriched CAR-T therapy compared to the CD19-specific CAR-T cells generated using a standard protocol where a high glucose medium was used throughout the ex vivo expansion. The impact of different bioreactor operating conditions on T cells growth and phenotypic composition was further investigated. Two different levels of Dissolved Oxygen (dO2; 25% and 90%), pH (6.9 and 7.4), and shaking speeds (100 rpm and 200 rpm), as well as the interaction between them were assessed. The results demonstrated that the optimal culture condition for generating a high number of CD8+ TCM cells is a combination of 200 rpm, 25% dO2, and pH of 7.4. This thesis highlights the importance of investigating the impact of metabolites in the medium and bioreactor parameters during the T cell therapies manufacturing in order to improve the quality and quantity of the final product.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Role of Metabolites and Bioreactor Operating Conditions on T Cell Manufacturing
Event: UCL (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 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 > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10127514
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