Development of experimentally-integrated process models for adaptive CAR-T cell therapy manufacturing

A new generation of gene-edited cell therapies have been developed which have the potential to cure certain aggressive types of cancer. Autolus, a leading biopharmaceutical company within this field, are genetically engineering patient's own immune cells (T-cells) in vitro to recognise and target cancerous cells. Following in vitro engineering, patient's T-cells express 'chimeric antigen receptors' (CARs) on their surface, which have been carefully constructed to allow the T-cells to by-pass cancerous cells' defence mechanisms. Recently two FDA approved autologous CAR-T therapies have shown remarkable clinical outcomes, with most patients receiving therapy in remission (some for 5 or more years post-administration).

However, the costly, inherently variable, sub-optimal, manual, and open manufacturing processes limit patient accessibility to these transformative therapies. To resolve these manufacturing challenges, it is necessary to compensate for the inherent variation in patient starting material and optimise production. An adaptive production system which measures and adapts to in-process measurements in real-time can achieve this. Such a system will require relevant, experimentally-derived process models. However, the use of such models is limited due to lack of robust experimental data, tools to support a structured approach, the difficulty of realising computationally tractable (low parameter) yet realistic models, and the specialised skill sets required.

This Industrial Fellowship will focus on establishing experimentally-driven process models for adaptive autologous CAR-T cell therapy manufacture with the aid of combined expertise and facilities at Autolus and University College London (UCL). The proposed project will enhance understanding of the CAR-T manufacturing process and product characteristics, as well as providing effective predictive in-process tools for process development. The Industrial Fellow will develop a specialised skillset that will be a valuable foundation for a future career in cell and gene therapies.

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.