Capsomidis, Anna; (2020) Chimeric Antigen Receptor engineered gamma delta T cells for neuroblastoma immunotherapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Gamma delta (γδ) T cells are a unique subset of lymphocytes that combine both innate and adaptive immune properties. They are primed for rapid function including tumour cell cytotoxicity, and following activation, have professional antigen presenting function. Chimeric antigen receptors (CARs) are synthetically engineered receptors that combine the specific antigen-binding region of a monoclonal antibody with a signalling domain responsible for T cell activation and cytotoxicity. Given the natural tissue tropism and innate cellular responses of γδ T cells, it was hypothesised that transduction with a CAR would enhance antigen-specific cytotoxicity, whilst maintaining direct antigen presenting function and the ability to migrate towards tumours. Using the tumour antigen GD2 as a model system, we demonstrated that Vδ1 and Vδ2 cells could be activated, propagated and transduced to sufficient number for use in clinical studies in paediatric patients. The addition of GD2-CAR, enhanced γδ T cell innate cytotoxicity through specific killing of GD2-expressing neuroblastoma cell lines. Migration towards tumour cells was not impaired by the presence of the CAR. Following activation, GD2-CAR transduced Vδ2 cells, retained the ability to take up exogenous tumour antigen, and cross-presented processed peptide to responder αβ T cells. This study provides evidence to support the emerging role of CAR γδ T cells as a safe and efficacious immunotherapy for neuroblastoma.

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