Cell therapies, which use human cells to restore, maintain, or improve the functioning of human tissues or organs, hold enormous potential for the treatment of a wide range of diseases and conditions, including a variety of cancers. While cell therapies have the potential to improve healthcare for millions of patients worldwide, manufacturing remains a major hurdle for clinical translation. Today's cell therapies manufacturing processes, which include the use of patient's own cells or donor cells to manufacture the therapeutic product, involve manual, labour-intensive and open processes that require highly-skilled personnel. This in turn leads to high process variability, risk of contamination and high manufacturing costs, all of which are major obstacles for cell therapies to realise their full potential and bring about widespread access to the global patient population. New technologies are urgently needed to develop reliable and robust manufacturing processes that ensure quality and consistency of cell therapy products at an economically viable cost. This project will develop an on-demand sensor and monitoring technology that will enable, for the first time, real-time, non-disruptive measurement of key biochemicals in cell culture media. These unprecedented capabilities will be enabled by an innovative microfluidic sensing platform comprising smart, switchable electrode-tethered nanobodies. In contrast with conventional offline analysis, the acquisition of real-time process data will allow immediate response to process variations, thus providing a fine level of process control. This is essential for the consistent production of high-quality therapeutic cells in high yields, independently of the patient's or donor's cells. It will provide an exceptional opportunity to implement fully automated, robust cell therapy culture processes and bring down production costs, ultimately delivering cost-effective and impactful therapeutics to patients in need.

By 2025 targeted biological medicines, personalised and stratified, will transform the precision of healthcare prescription, improve patient care and quality of life. Novel manufacturing solutions have to be created if this is to happen. This is the unique challenge we shall tackle. The current "one-size-fits-all" approach to drug development is being challenged by the growing ability to target therapies to only those patients most likely to respond well (stratified medicines), and to even create therapies for each individual (personalised medicines). Over the last ten years our understanding of the nature of disease has been transformed by revolutionary advances in genetics and molecular biology. Increasingly, treatment with drugs that are targeted to specific biomarkers, will be given only to patient populations identified as having those biomarkers, using companion diagnostic or genetic screening tests; thus enabling stratified medicine. For some indications, engineered cell and gene therapies are offering the promise of truly personalised medicine, where the therapy itself is derived at least partly from the individual patient. In the future the need will be to supply many more drug products, each targeted to relatively small patient populations. Presently there is a lack of existing technology and infrastructure to do this, and current methods will be unsustainable. These and other emerging advanced therapies will have a critical role in a new era of precision targeted-medicines. All will have to be made economically for healthcare systems under extreme financial pressure. The implications for health and UK society well-being are profound There are already a small number of targeted therapies on the market including Herceptin for breast cancer patients with the HER2 receptor and engineered T-cell therapies for acute lymphoblastic leukaemia. A much greater number of targeted therapies will be developed in the next decade, with some addressing diseases for which there is not currently a cure. To cope, the industry will need to create smarter systems for production and supply to increasingly fragmented markets, and to learn from other sectors. Concepts will need to address specific challenges presented by complex products, of processes and facilities capable of manufacture at smaller scales, and supply chains with the agility to cope with fluctuating demands and high levels of uncertainty. Innovative bioprocessing modes, not currently feasible for large-scale manufacturing, could potentially replace traditional manufacturing routes for stratified medicines, while simultaneously reducing process development time. Pressure to reduce development costs and time, to improve manufacturing efficiency, and to control the costs of supply, will be significant and will likely become the differentiating factor for commercialisation. We will create the technologies, skill-sets and trained personnel needed to enable UK manufacturers to deliver the promise of advanced medical precision and patient screening. The Future Targeted Healthcare Manufacturing Hub and its research and translational spokes will network with industrial users to create and apply the necessary novel methods of process development and manufacture. Hub tools will transform supply chain economics for targeted healthcare, and novel manufacturing, formulation and control technologies for stratified and personalised medicines. The Hub will herald a shift in manufacturing practice, provide the engineering infrastructure needed for sustainable healthcare. The UK economy and Society Wellbeing will gain from enhanced international competitiveness.

For the last half-century doctors have routinely used radioactive drugs - radiopharmaceuticals - to detect and diagnose disease in patients and to treat cancer. This speciality is known as nuclear medicine. Modern imaging with radiopharmaceuticals is known as molecular imaging, and treating cancer with them is known as radionuclide therapy. Currently there are economic and geographical barriers, both in the UK and overseas, for patients accessing these scans and treatments. Our programme will develop technologies to perform both molecular imaging and radionuclide therapy more cost-effectively, benefitting more patients and greatly enhancing quality of information, depth of understanding of the disease, and therapeutic benefit. We will use new chemistry to make synthesis of the radiopharmaceuticals faster, more cost-effective and usable in more locations, and hence more accessible for patients. It will improve healthcare by producing and clinically translating new radioactive probes for positron emission tomography (PET), single photon emission computed tomography (SPECT) and radionuclide therapy, to harness the potential of emerging new scanners and therapeutic radionuclides, and provide a diagnostic foundation for emerging advanced therapies. Advanced medicines such as cell-based and immune therapies, targeted drug delivery and radionuclide therapy pose new imaging challenges such as personalised profiling to optimise benefit to patients and minimise risk, and tracking the fate of drug/radionuclide carriers and therapeutic cells in the body. New alpha-emitting radionuclides for cancer therapy are impressing in early trials. New understanding of cancer heterogeneity shows that imaging a single molecular process in a tumour cannot predict treatment outcome. New generation scanners such as combined PET-MR are finding clinical utility, creating niche applications for combined modality tracers; new gamma camera designs and world-wide investment in production of technetium-99m, the staple raw material for gamma camera imaging, demand a new generation of technetium-99m tracers; and "total body PET" will emerge soon, enhancing the potential of long-lived radionuclides for cell and nanomedicine tracking. Demand for new tracers is thus greater than ever, but their short half-life (minutes/hours) means that many of them must be synthesised at the time and place of use. Except for outdated technetium-99m probes, current on-site syntheses are complex and costly, limiting availability, patient access and market size, particularly for modern biomolecule-based probes. Therefore, to grasp opportunities to improve healthcare afforded by the aforementioned advances in therapies and scanners, they must be matched by new chemistry for tracer synthesis. This Programme will dramatically enhance patient access to molecular imaging and radionuclide therapy in both developed and low/middle-income countries, by developing and biologically evaluating faster, simpler, more efficient, kit-based biomolecule labelling with radioactive isotopes for imaging and therapy, streamlining production and reducing need for costly and complex automated synthesisers. In addition, it will maximise future impacts of total body PET, SPECT, PET-MR by evaluating and developing the potential of multiplexed PET to harness the full potential of total body PET: combined imaging of multiple molecular targets, not just one, using fast chemistry for several very short half-live tracers in tandem in a single session to offer a new level of personalised medicine. The programme will also enable the tracking of nanomedicines and cells within the body using long half-life radionuclides - an area where total body PET and PET-MR will be transformative). Finally, we will secure additional funding of selected probes into clinical use in heart disease, cancer, inflammation and neurodegenerative disease.

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.

This proposal bids for £4.5M to both evolve and renew the Loughborough, Nottingham and Keele EPSRC CDT in Regenerative Medicine. The proposal falls within the 'Healthcare Technologies' theme and 'Regenerative Medicine' priority of the EPSRC call. This unique CDT is fully integrated across three leading UK Universities with complementary research profiles and a long track record of successful collaboration delivering fundamental and translational research. Cohorts of students will be trained in the core scientific, transferable, and translational skills needed to work in this emerging healthcare industry. Students will be engaged in strategic and high quality research programmes designed to address the major clinical and industrial challenges in the field. The CDT will deliver the necessary people and enabling technologies for the UK to continue to lead in this emerging worldwide industry.The multidisciplinary nature of Regenerative Medicine is fully captured in our proposal combining engineering, biology and healthcare thereby spanning the remits of the BBSRC and MRC, in addition to meeting EPSRC's priority area.