Chan, Choi Yee; (2024) 3D Biomimetic Scaffolds for In Vitro γδ T Cell Expansion. Doctoral thesis (Ph.D), UCL (University College London).

Text Final_Chan Choi Yee_14013963_PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 November 2025. Download (359MB)

Abstract

Gamma delta (γδ) T cells have both innate and adaptive immune properties. Their ability to recognise a wide range of antigens without relying on the major histocompatibility complex makes them an alluring option to be developed into potent, off-the-shelf T cell therapies. However, current methods for expanding γδ T cells solely using biological stimuli have hindered efforts to scale up production for commercial allogeneic applications. The conventional 2D flat-plate system, though once seen as ideal for growing T cells in the lab, is not practical for meeting large-scale clinical demands. Since late 1990s, co-stimulation with cytokines and collagen have been reported to greatly enhance the growth and functionality of alpha-beta (αβ) T cells. Although γδ T cells are considered as non-adherent, collagen-based microcarriers may still be beneficial by providing physical cues that enhance their proliferation and cytotoxicity. Incorporating the microcarriers in stirred-tank bioreactors could aid the future scale-up allogeneic γδ T cell production as this approach is considered a well-established technique in bioprocessing where the system offers control over environment and are easily scalable, making them ideal for mass production in cell therapies. In this work, extra cellular matrix (ECM)-mimicking collagen coated microcarriers were found to amplify the activated γδ T cell quantity after 2 weeks compared to the conventional expansion protocol solely utilising biological activation and stimulation by zoledronic acid and interleukin-2 under static condition. An intensified cell growth was sustained following the one week incubation extension without upregulation in exhaustion marker - Programmed cell death protein 1. Via flow cytometry and killing assays, the activated γδ T cells’ subset expression along with their functional phenotypes and cancer killing capability were not obstructed by the scaffold implementation. Under the identical activation and stimulation of zoledronic acid and interleukin-2, a noticeable escalation in the γδ T cell expansion induced by the presence of collagen coated microcarriers was also recorded in the preliminary scaled-up dynamic expansion study. Our data thus suggested the selected biomimetic scaffold holds the potential to be developed as a novel scalable expansion platform which is capable to amplify the γδ T expansion capacity whilst retaining comparable functional capability.

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