3D scaffolds for the activation of CAR-T cell growth

Background: CAR-T cell have recently been identified for the treatment of late-stage leukaemia. The production of CAR-T cells involves expanding cells in the presence of anti CD3/CD28 magnetic beads. Affinity based magnetic beads suffer from a number of drawbacks. They can easily be taken up by the target cells and are difficult to remove from the final product leading to the presence of an unwanted contaminant. In addition a relatively high number of binding events are needed to magnetise the cells making inefficient usage of expensive antibodies and driving up manufacturing costs. UCL Biochemical Engineering have been collaborating with Spheritech to produce large beads for the purification retinal cells derived from differentiated iPSC as an alternative to magnetic bead and fluorescent-activated cell sorting (FACS).

The aim of this project is to establish Spheritech's polymer technologies as a viable alternative to CD3/CD28 magnetic beads. Specific objectives will include establishing a model reprogramming process based on lentiviral mediated GFP expression in commercially available T-cells and evaluation of polymer and antibody fragment alternatives to CD3/CD38. We will also characterise ligand binding to a number of Spheritech's polymer platforms and
test polymer-ligand activation of T-Cells. In the later stages of the project we will use Synthetic Biology approaches to modify cartridge construction and also explore optimisation of cartridge operating conditions for T-Cell activation.

Significance and Impact
Engineered cell therapies such as CAR-T cells represent a new tool for fighting cancer. Early clinical data has been very encouraging with a high proportion of late stage leukaemia patients reporting long-term reversal of the disease. Unfortunately, progress in the clinic has not been mirrored by improvements in the production costs. Expensive antibodies used for the activation T-cells must be used more efficiently in order to drive down raw material costs. The application of Spheritech's polymer technology will dramatically reduce the amount of antibody required to treat a single patient establishing a new and potentially lucrative market for this SME.

The IDC 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 graduates; (ii) generation of intellectual property (IP) in support of collaborating companies or for new venture 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 wider society via involvement in public engagement activities and encouraging future generations of researchers.

With regard to training, the provision of future bioindustry leaders is the primary mission of the IDC and some 97% of previous EngD graduates have progressed to relevant bioindustry careers. These highly skilled individuals help catalyse the development and expansion of private sector innovation and biomanufacturing activity. This is of enormous importance to capitalise on emerging markets and to create new jobs and a skilled labour force to underpin the UK economy.

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 this has the potential to lead to spin-out company creation and job creation with wider UK economic benefit. IDC research has already led to creation of two UCL spin-out companies focussed on the emerging field of Synthetic Biology (Synthace) and novel nanofibre adsorbents for improved bioseparations (Puridify). Once arising IP is protected the IDC also provides a route for wider dissemination of project outputs and knowledge exchange available to all UK bioprocess-using companies. This occurs via UCL MBI Training Programme modules which have been attended by more than 1000 individuals from over 250 companies to date.

The majority of IDC projects address production of new medicines or process improvements for pharmaceutical or biopharmaceutical manufacture which directly benefit healthcare providers and patients. Examples arising from previous EngD projects have included: engineered enzymes used in the synthesis of a novel pharmaceutical; early stage bioprocess development for a new meningitis vaccine; redevelopment of the bioprocess for manufacture of the UK anthrax vaccine; and establishment of a cGMP process for manufacture of a tissue-engineered trachea (this was subsequently transplanted into a child with airway disease and the EngD researcher was featured preparing the trachea in the BBC's Great Ormond Street series). Each of these examples demonstrates IDC impact on the development of cost-effective new medicines and therapies. These will benefit society and provide new tools for the NHS to meet the changing requirements for 21st Century healthcare provision.

Finally, in terms of wider public engagement and society, the IDC has achieved substantial impact via involvement of staff and researchers in activities with schools (STEMnet, HeadStart courses), 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 IDC researchers will be increasingly involved in such outreach activities to explain how the potential economic and environmental benefits of Synthetic Biology can be delivered safely and responsibly.