The most significant healthcare challenge facing the UK is the unavoidable transition towards an older, ageing population, resulting in an increased demand for hospital and social care, complex medical interventions, spiralling costs and increased societal burden. The development of new, affordable and effective medicines will therefore be necessary to ensure we maintain and improve the standard of UK and global healthcare. A new type of medicine, advanced cell and gene therapy (CGT), has recently emerged as a promising treatment option for previously incurable conditions. CGTs will form the next-generation of advanced medicines with the potential to improve UK health and wealth. Examples of CGTs include cellular immunotherapies. These are medicines which use genetically-engineered cells to target cancer cells. Chimeric antigen receptor natural killer cell therapies (CAR-NK) are an example of a cellular immunotherapy. Natural killer cells are a key immune cell type that fights infections in our bodies, however, we can genetically-engineer them to express a non-native protein (the CAR) which allows the NK-cells to target and eliminate blood cancer cells, an ability they only possess because of the non-native CAR protein. These gene-modified therapies have demonstrated remarkable clinical success and offer a revolutionary approach to treat patients who have failed every other treatment option (e.g. chemotherapy, bone marrow transplant) and are ultimately destined to die of their disease. However, this new treatment option has resulted in dramatic outcomes, with patients in complete remission for years after receiving the therapy. It has effectively cured patients of their cancer. However, despite their clinical promise, approved immunotherapies suffer from high costs (>$350,000 per dose), poorly defined manufacturing processes and challenging gene engineering approaches involving the use of expensive and complex viruses as vehicles for gene delivery. Without significant manufacturing innovations, the promise of these transformative, curative therapies will not be realised, and they will remain inaccessible to the vast majority of patients that need them. The implications for UK health, wealth and well-being are profound. My Fellowship focuses on establishing a scalable manufacturing process for CAR-NK therapies and demonstrating the first litre-scale production for CAR-NK cells. This will be achieved by creating an innovative and intelligent control strategy to improve the production process and increase the number of cells that can be manufactured. We will use scientific and engineering approaches to understand how the cellular environment can be made more conducive to encourage cell growth, specifically monitoring and controlling the environmental conditions (e.g. gases, nutrients, temperature, pH) to support optimal cell production. We will establish the process conditions and technologies that are required to grow and generate sufficient numbers of cells for clinical applications. We will also develop a new way to engineer the cells using an approach that doesn't require the use of viruses (a non-viral approach) which is based on mechanical and chemical methods. My Fellowship research programme will support the industrial and clinical communities to deliver this next-generation of advanced medicines to treat patients in the UK and ensure these therapies are accessible to the patients that need them at a price that is affordable for the UK health system to bear. This will also support the development of the growing cell and gene therapy manufacturing industry in the UK and support economic activity in the high-growth biomanufacturing sector.

The UK government's support for the Life Sciences Industry Strategy (Bell Report, 2017) recognises the importance of developing new medicines to facilitate UK economic growth. Examples include new antibody therapies for the treatment of cancer, new vaccines to control the spread of infectious diseases and the emergence of cell and gene therapies to cure previously untreatable conditions such as blindness and dementia. Bioprocessing skills underpin the safe, cost-effective and environmentally friendly manufacture of this next generation of complex biological products. They facilitate the rapid translation of life science discoveries into the new medicines that will benefit the patients that need them. Recent reports, however, highlight specific skills shortages that constrain the UK's capacity to capitalise on opportunities for wealth and job creation in these areas. They emphasise the need for 'more individuals trained in advanced manufacturing' and for individuals with bioprocessing skills who can address the 'challenges with scaling-up production using biological materials'. The UCL EPSRC CDT in Bioprocess Engineering Leadership has a successful track record of equipping graduate scientists and engineers with the bioprocessing skills needed by industry. It will deliver a 'whole bioprocess' training theme based around the core fermentation and downstream processing skills underpinning medicines manufacture. The programme is designed to accelerate graduates into doctoral research and to build a multidisciplinary research cohort; this will be enhanced through a partnership with the Synthesis and Solid State Pharmaceutical Centre (SSPC) and the National Institute for Bioprocess Research and Training (NIBRT) in Ireland. Research projects will be carried out in partnership with leading UK and international companies. The continued need for the CDT is evidenced by the fact that 96% of previous graduates have progressed to relevant bioindustry careers and many are now in senior leadership positions. The next generation of molecular or cellular medicines will be increasingly complex and hence difficult to characterise. This means they will be considerably more difficult to manufacture at large scale making it harder to ensure they are not only safe but also cost-effective. This proposal will enable the CDT to train future bioindustry leaders who possess the theoretical knowledge and practical and commercial skills necessary to manufacture this next generation of complex biological medicines. This will be achieved by aligning each researcher with internationally leading research teams and developing individual training and career development programmes. In this way the CDT will contribute to the future success of the UK's bioprocess-using industries.