Data-driven experimental approach to increase transfection efficiency and prolonging vector production in transient systems

The production of lentiviral vector (LVV) has been critical for the emergence of ex vivo gene-modified cellular therapies, such as chimeric antigen receptor T cells (CAR-T). However, it is widely recognised that there are global limitations on both capacity and capability.

One of the key manufacturing challenges for LVV is the limitations around the transfection process and enabling prolonged production. The project is focused on developing a data-driven experimental approach to achieve an optimal bioprocess which results in higher lentiviral (LV) transfection efficiencies and/or prolonged LV production compared to the current gold standard process.

The approach this project will adopt is to combine the power of high-throughput experimental studies in combination with machine-learning based approaches to identify the optimal factors for improved transfection efficiency. Following the systematic ranking of key variables and the establishment of the design space, experimental studies will be undertake to explore the design space of factors. Throughout the course of the experimental work, periodic scale-up work will be undertaken to confirm scalability of the small-scale studies and findings. Moreover, investigations will be undertaken to asses the impact the upstream optimisation on downstream processing.

This project has potential to significantly enhance and improve the production of LVV and ensure that large quantities of functional vector are made available for the next generation of advanced therapeutics. This project is aligned closely to EPSRC's Manufacturing the Future research theme which focuses on researching and developing high-value manufacturing capability and capacity for the UK.

The CDT has a proven track record of delivering impact from its research and training activities and this will continue in the new Centre. The main types of impact relate to: (i) provision of highly skilled EngD and sPhD graduates; (ii) generation of intellectual property (IP) in support of collaborating companies or for spin-out company creation; (iii) knowledge exchange to the wider bioprocess-using industries; (iv) benefits to patients in terms of new and more cost effective medicines, and (v) benefits to the wider society via involvement in public engagement activities and impacts on policy.

With regard to training, provision of future bioindustry leaders is the primary output of the CDT and some 96% of previous EngD graduates have progressed to relevant bioindustry careers. These highly skilled individuals help catalyse private sector innovation and biomanufacturing activity. This is of enormous importance to capitalise on emerging markets, such as Advanced Therapy Medicinal Products (ATMPs), and to create new jobs and a skilled labour force to underpin economic growth. The CDT will deliver new, flexible on-line training modules on complex biological products manufacture that will be made available to the wider bioprocessing community. It will also provide researchers with opportunities for international company placements and cross-cohort training between UCL and SSPC via a new annual Summer School and Conference.

In terms of IP generation, each industry-collaborative EngD project will have direct impact on the industry sponsor in terms of new technology generation and improvements to existing processes or procedures. Where substantial IP is generated in EngD or sPhD programmes, this has the potential to lead to spin-out company creation and job creation with wider economic benefit. CDT research has already led to creation of a number of successful spin-out companies and licensing agreements. Once arising IP is protected the existing UCL and NIBRT post-experience training programmes provide opportunities for wider industrial dissemination and impact of CDT research and training materials.

CDT projects will address production of new ATMPs or improvements to the manufacture of the next generation of complex biological products that will directly benefit healthcare providers and patients. Examples arising from previous EngD projects have included engineered enzymes for greener pharmaceutical synthesis, novel bioprocess operations to reduce biopharmaceutical manufacturing costs and the translation of early stem cell therapies into clinical trials. In each case the individual researchers have been important champions of knowledge exchange to their collaborating companies.

Finally, in terms of wider public engagement and society, the CDT has achieved substantial impact via involvement of staff and researchers in activities with schools (e.g. STEMnet), presentations at science fairs (Big Bang, Cheltenham), delivery of high profile public lectures (Wellcome Trust, Royal Institution) as well as TV and radio presentations. The next generation of CDT researchers will receive new training on the principles of Responsible Innovation (RI) that will be embedded in their research and help inform their public engagement activities and impact on policy.