Award details

Developing generic scalable and standardised selection methods for human therapeutic cells

Reference	BB/I017151/1
Principal Investigator / Supervisor	Dr Mark Cobbold
Co-Investigators / Co-Supervisors	Professor Owen Thomas, Professor Suzanne Watt
Institution	University of Birmingham
Department	Immunity and Infection
Funding type	Research
Value (£)	441,415
Status	Completed
Type	Research Grant
Start date	01/09/2011
End date	30/09/2014
Duration	37 months

Abstract

The broad aims of this project proposal are to advance two new high-throughput, single-use cell selection systems in parallel, namely a 'reverse engineered' cell selection device based on hollow fibre dialysis cartridges with the capability of capturing cells ex vivo or in vivo, together with ex vivo cellular chromatographic systems exploiting cast polymer monoliths featuring derivatised giant convective pores (Gigaporous hydrogel monoliths or GHMs). Our intention is to keep the technologies generic to allow industrial partners to develop them for use in selecting many different cell types, but careful consideration to current regulatory constraints for cellular therapy will guide development. In developing the above affinity cell selection systems, we shall employ monoclonal antibodies, cell lines and three major sources for the primary cells, i.e. heparinised whole peripheral or cord blood; leukapheresis products from routine collection machines. This work will culminate in a pre-clinical model of human endothelial stem cell xenotransplantation to assess the efficacy of the cell selection technology. Revascularisation represents a critical component of tissue repair, with autologous endothelial stem/progenitor cells, their pro-angiogenic counterparts and the products of these cells all being attractive targets for therapeutic intervention.

Summary

This proposal aims to deliver practical, scientific and technologically innovative solutions to a real problem through partnership between neighbouring Universities: the University of Birmingham, Loughborough University and the University of Oxford. We aim to develop a device to allow blood cells to be selected directly from the blood. This device would allow new treatments to meet the bioselection challenges presented by advanced cellular therapies. Effective cellular therapies are not new and date back to 1665 when the first successful blood transfusion took place. Today, 81 million units of blood are taken each year, saving hundreds of thousands of lives worldwide. In addition, at least 50,000 patients receive stem cell transplants (SCT; also known as Bone Marrow Transplants) globally every year (one of the few therapies able to cure individuals with cancer) with each costing around £100,000. The blood stem cells account for only 0.2% of all white blood cells in the blood. Unfortunately it is not possible to isolate just the stem cells from blood, but instead, a large number of white cells are removed from the donor's blood via a process termed leukapheresis. The donor quickly replenishes their white cells over the next few weeks. One side effect for the donor is that their bone marrow is stimulated to grow which frequently leads to bone pain. These stem cells potentially offer the gift of life to the recipient who typically will have leukaemia or lymphoma where these cells migrate to the bone marrow and start producing blood for the patient. However some of the white blood cells from the donor have to potential to cause harm, these immune cells recognise the recipient as foreign and try to attack them. To prevent this, the stem cells are purified from the white cells and infused in a purer form. Scientists are understanding more about stem cells then ever before and can now expand these rare cells in the laboratory and even create new organs from them (in mice at least). The challenge now is to bring these new techniques and knowledge to the forefront of clinical medicine. Before this can be done, new technologies are required to manipulate these cells in a manner that will not introduce infection and ensures the cells are of sufficiently high quality to be effective for the patient. The aim of this proposal is to develop a new device which would allow the enrichment of cells. The device will be engineered to be very versatile and would allow the enrichment of any cell type and thus will be of broad interest to many companies seeking to develop cellular therapies. We propose two steps, first a 'capture' device which could even be used to directly isolate cells from the circulating blood of a donor/patient. This could reduce side effects of stem cell isolation such as the bone pain by only picking out the cells of interest. The next step would be to wash these captured cells and pass them over smaller purification columns, which would remove unwanted cell types and capture the cells of interest. This is important as currently there are no ways to select subpopulations of cells. Finally the cells will be released and analysed for their properties. This work has been principally developed by a clinician familiar with the problems delivering new therapeutics to the clinical coalface. We have a working prototype able to capture and release cells from whole blood and are asking for funding to develop this further. We have designed the device with the NHS in mind, to be safe, effective and importantly affordable.

Impact Summary

This work aims to deliver new tools for downstream processing of cellular therapies, or cells for the production therapeutic biologics. Current technologies for bioseparation are ill-suited for multi-step enrichment of cells and over-reliant on magnetic selection. As such this proposal seeks to develop a device able to select cells whilst conforming to current regulatory constraints. Throughout the design stage, the device will be engineered to have a generic configuration allowing the end user to customise the selection device such that it will select the cell, or even viral particle, of interest. The principal beneficiaries of this work will be the biopharmaceutical and medical communities, as such systems will enable 'breakthroughs' in regenerative medicine reaching the clinic and may reduce costs. Beneficiaries will also include the global academic community in the field of cellular therapies. The ultimate beneficiaries will be patients with organ failure or degenerative illnesses, as this work will hopefully facilitate such therapies reaching the clinic in a timely manner. Patients, for the first time, could have autologous stem cells cultured in bioreactors ex-vivo, which could be expanded and differentiated in vitro into various cellular tissue cell types and used to populate decellularised organ scaffolds. These organs could be engrafted into the recipient without risk or fear of immune-mediated rejection. If successful, this platform may provide a number of far-reaching socio-economic benefits to the United Kingdom, and perhaps to the global healthcare, biopharmaceutical and bioprocessing community. This proposal, if funded will train at least 2 postdoctoral fellows and in turn support at least 2 PhD studentships, and likely at least one clinical research fellow. This work will increase our understanding of cellular selection and in particularly knowledge of macroporous hydrogel cellular selection, which are relatively new biomaterials with uncharacterised biocellular interaction dynamics. Another consideration, whilst outside the scope of this proposal, may be the impact of regenerative medicine on society. Significant ethical consideration, particularly if using allogeneic embryonic stem cells derived from human embryos, will need to be considered. Strong political leadership and policy-making, in addition to excellent scientific engagement with the public will be required from an early stage. Consideration will need to be given to religious and cultural beliefs particularly in a multicultural society such as the UK. Lastly, in addition to bringing considerably healthcare benefits, regenerative medicine has significant potential to widen healthcare inequalities. The provision of life-extending cellular therapies which are prohibitively expensive for the NHS or the majority of the population could lead to social unrest. These arguments re-enforce the importance of engaging with the public at an early stage, and by developing such products from within the healthcare providers such as the NHS, NHSBT and the public sector (universities). Inevitably, as with almost all technologies, the scale of the benefit and nature of the ultimate beneficiaries can be very hard to predict at the outset. Unexpected discoveries or turn of events, often by chance, lead to new directions and new opportunities.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Industrial Biotechnology, Pharmaceuticals, Regenerative Biology, Stem Cells, Technology and Methods Development
Research Priority	Technology Development for the Biosciences
Research Initiative	Bioprocessing Research Industry Club (BRIC) [2006-2012]
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/I017143/1 Developing generic scalable and standardised selection methods for human therapeutic cells

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