O'Reilly, Maeve; (2023) Development and Clinical Implementation of Next-Generation CAR-T cell Manufacture Methodology. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Chimeric Antigen Receptor (CAR) T-cell therapies for haematological malignancy have revolutionised the treatment of patients with relapsed/refractory B-cell cancers. The scope of these therapies in other haematological and even solid cancers holds much promise for the future. However, there are several major bottlenecks for delivery of these novel therapies: availability of academic clinical trials for CAR T-cell therapies is limited in the UK and in particular, the paucity of manufacturing slots means that the majority of potentially eligible patients cannot access these therapies. Streamlining the manufacturing process and pipeline to enhance manufacturing capability and scalability would begin to address this challenging issue. Secondly, a large proportion of patients referred for consideration of autologous CAR T-cell therapy are heavily pre-treated with chemotherapy and their T-cell populations for harvest are often numerically (and in some cases functionally) compromised. Referring patients early, prior to several lines of toxic chemotherapy would be optimal, but this is logistically challenging. Another approach would be to review apheresis practice and work to enhance T-cell collection at the front end. Lastly, these new therapies are associated with a constellation of unique potential side effects. The clinical delivery of bespoke gene-modified T-cell therapies in routine Haemato-Oncology Units requires a paradigm shift in medical, nursing, pharmacy and stem cell lab care pathways. This project undertakes to address these issues through the initiation and delivery of an academic study of autologous CD19 CAR T-cells for relapsed/refractory acute lymphoblastic leukaemia (B-ALL). This project will (1) investigate and establish a streamlined manufacturing platform for CAR T-cell manufacture for the UCL CAR T-cell programme; (2) explore the single-centre apheresis practice at UCLH to define a model/guideline for successful CAR T-cell apheresis and (3) to begin to establish the clinical infrastructure required to deliver these therapies ‘routinely’ at a large central London teaching hospital.

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