Engineering Biological Science - Processes and Systems for Haematopoietic Stem Cell Based Therapy Manufacture
Lead Research Organisation:
Loughborough University
Department Name: Wolfson Sch of Mech, Elec & Manufac Eng
Abstract
Umbilical cords are traditionally discarded after childbirth as medical waste. However, over the past few decades it has become apparent that the cord contains a small amount of immature blood cells with powerful properties to repair the human body. Cord blood is now frequently used instead of bone marrow to treat childhood blood cancers (leukaemia). Cord blood cells can also be grown to generate very large numbers of red blood cells or platelets for transfusion, or, if processed differently to create immune system cells. More recently cord blood has been proven effective, or is being clinically trialled, for a wide range of serious conditions such as organ failure, childhood brain damage or diabetes.
Despite national cord blood collection and banking programmes since the early 1990's, the success of these new clinical applications will lead to unsustainable demand on already strained stocks of cord blood. In this Fellowship I intend to develop tools to help manufacture large quantities of medicinally valuable cord blood cells from the small samples retrieved at child birth. This will form the basis of a manufactured blood related bio-products industry.
We will use a new technology to grow the cells in small vessels under very controlled conditions. These vessels will let us quickly and efficiently test different physical conditions (such as oxygen and acidity) and novel chemical additives on the growth of the blood cells. We will use engineering approaches to control the cells' environment in novel ways, and understand the relationships between the cells' development. We will demonstrate the conditions and systems that are necessary to grow these cells to large and clinically useful numbers. We will also understand how tolerant the manufacturing process is for repeated production of safe and effective cells.
My proposed research will help the clinical community deliver a new cohort of treatments for serious diseases to patients in the UK as well as help develop an important new economic activity in the UK in the development of these new types of cell based therapies.
Despite national cord blood collection and banking programmes since the early 1990's, the success of these new clinical applications will lead to unsustainable demand on already strained stocks of cord blood. In this Fellowship I intend to develop tools to help manufacture large quantities of medicinally valuable cord blood cells from the small samples retrieved at child birth. This will form the basis of a manufactured blood related bio-products industry.
We will use a new technology to grow the cells in small vessels under very controlled conditions. These vessels will let us quickly and efficiently test different physical conditions (such as oxygen and acidity) and novel chemical additives on the growth of the blood cells. We will use engineering approaches to control the cells' environment in novel ways, and understand the relationships between the cells' development. We will demonstrate the conditions and systems that are necessary to grow these cells to large and clinically useful numbers. We will also understand how tolerant the manufacturing process is for repeated production of safe and effective cells.
My proposed research will help the clinical community deliver a new cohort of treatments for serious diseases to patients in the UK as well as help develop an important new economic activity in the UK in the development of these new types of cell based therapies.
Planned Impact
Ex vivo control of proliferation and development of HSCs will create the opportunity for rapid clinical impact for patients suffering from haematological malignancies through a safe and unlimited supply of immunologically matched and consistent quality cells engineered to increase engraftment speed and decrease mortality. It will provide the scientific basis for a fully self-replenishing input cell supply for industrial production of naturally occurring haematopoietic lineages or haematopoietic cells engineered for therapeutic effect. This 'productisation' of cells will drive down costs for health service suppliers, create a manufacturing paradigm with sufficient economic return for product manufacturers, contribute to economic growth in a strategic area for the UK economy (high value bio-manufacturing), and create a UK technology based industry for export. It will bolster research into other therapeutic applications, such as organ support, through offering reproducible cells specifications for clinical trials. It will hasten the reality of manufactured cellular blood products and their manipulation for diverse therapeutic outcomes. The science developed will provide a powerful case study of the potential of interdisciplinary research and provide a pathway for other complex cell therapy developments with detrimental emergent parameters in bio-manufacture.
Organisations
- Loughborough University (Fellow, Lead Research Organisation)
- Advanced Bioprocess Design Ltd (Collaboration)
- NHS National Services Scotland (NSS) (Collaboration)
- Advanced Bioprocess Services Ltd (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Fred Hutchinson Cancer Research Center (Project Partner)
- Sartorius (United Kingdom) (Project Partner)
People |
ORCID iD |
Robert Thomas (Principal Investigator / Fellow) |
Publications
Worrallo MJ
(2017)
Immobilized hematopoietic growth factors onto magnetic particles offer a scalable strategy for cell therapy manufacturing in suspension cultures.
in Biotechnology journal
Stacey A
(2018)
Experimentally integrated dynamic modelling for intuitive optimisation of cell based processes and manufacture
in Biochemical Engineering Journal
Smith D
(2016)
Automated image analysis with the potential for process quality control applications in stem cell maintenance and differentiation.
in Biotechnology progress
Moore RLL
(2017)
Immobilisation of Delta-like 1 ligand for the scalable and controlled manufacture of hematopoietic progenitor cells in a stirred bioreactor.
in BMC biotechnology
Hallam D
(2018)
Human-Induced Pluripotent Stem Cells Generate Light Responsive Retinal Organoids with Variable and Nutrient-Dependent Efficiency.
in Stem cells (Dayton, Ohio)
Granja C
(2020)
A quartz crystal resonator for cellular phenotyping
in Biosensors and Bioelectronics: X
Glen K
(2018)
A mechanistic model of erythroblast growth inhibition providing a framework for optimisation of cell therapy manufacturing
in Biochemical Engineering Journal
Bayon Y
(2014)
Translating cell-based regenerative medicines from research to successful products: challenges and solutions.
in Tissue engineering. Part B, Reviews
Bayley R
(2018)
The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors.
in Journal of tissue engineering and regenerative medicine
Description | The research has developed a mechanism for presentation of soluble proteins in an immobilised form for scalable application in bioreactors and manipulation independently from other soluble medium components. A modelling framework has been developed and captured within a software interface specifically for modelling bioprocesses and their specific operational traits. The modelling has been used to identify limiting operational factors for cell productivity; this has enabled us to specify the volume productivity limits of current systems and also to engineer improvements that deliver more than 3x improvement in system volume productivity. |
Exploitation Route | Our findings are currently being applied and evaluated by multiple commercial partners for application in industrial manufacture processes, including inclusion in a recent clinical production protocol for a novel class of cell based therapeutic product. |
Sectors | Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Description | The efficiency and control outcomes that we are demonstrating in cell culture in the academic setting have shown the potential to significantly reduce bio-manufacturing run times and to dramatically reduce total volume requirements. Our findings are currently being applied by a US based partner company to build an efficient manufacturing process for a very high dose cell based therapeutic product. The impact of our work will make the difference between unfeasible final manufacturing costs and a product that will have real clinical impact. The work is also being evaluated by selected UK partners for potential exploitation. This has enabled, over a period from 2016 to 2021, the establishment of an industrially funded activity within the University attracting over 500,000 GBP of direct funding to the institution. Furthermore, the manufacturing expertise is now embedded in an independent contract research organisation with international partners and in excess of 1M GBP annual turnover as of 2020/2021. Our ambition is that as the modelling and process design approaches we are developing are demonstrated in these early real world industrial case studies that the evident benefits will lead to wider take up across the industry, and this is increasingly evdiecned through the work of our embedded CRO. |
First Year Of Impact | 2016 |
Sector | Manufacturing, including Industrial Biotechology |
Impact Types | Economic |
Description | CCMI Scale-Up and Challenges in Manufacturing of ATMP workshop |
Geographic Reach | Europe |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Advanced Bioprocess |
Amount | £75,311 (GBP) |
Organisation | Advanced Bioprocess Services Ltd |
Sector | Private |
Country | United Kingdom |
Start | 06/2017 |
End | 12/2017 |
Description | Advanced Bioprocess 2 |
Amount | £100,973 (GBP) |
Organisation | Advanced Bioprocess Services Ltd |
Sector | Private |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2018 |
Description | Advanced Bioprocess 3 |
Amount | £41,333 (GBP) |
Organisation | Advanced Bioprocess Services Ltd |
Sector | Private |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2019 |
Description | CRACKIT [UK Industry] |
Amount | £96,066 (GBP) |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 01/2017 |
End | 06/2017 |
Description | Cell Therapy Manufacturing |
Amount | £192,717 (GBP) |
Organisation | Advanced Bioprocess Services Ltd |
Sector | Private |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2025 |
Description | Early Career Forum Call |
Amount | £45,420 (GBP) |
Funding ID | EP/L015404/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2014 |
End | 03/2016 |
Description | FUTURE MANUFACTURING HUB IN TARGETED HEALTHCARE |
Amount | £10,317,090 (GBP) |
Funding ID | EP/P006485/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2017 |
End | 12/2023 |
Description | Modelling Pluripotent Stem Cell Manufacture - Industrial Studentship |
Amount | £130,211 (GBP) |
Organisation | Advanced Bioprocess Services Ltd |
Sector | Private |
Country | United Kingdom |
Start | 04/2019 |
End | 03/2022 |
Description | Responsive Mode Manufacturing the Future |
Amount | £406,203 (GBP) |
Funding ID | EP/R031649/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2018 |
End | 11/2021 |
Description | The Pluripotent Stem Cells and Engineered Cell (PSEC) Hub |
Amount | £4,095,179 (GBP) |
Funding ID | MR/R015724/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2018 |
End | 05/2024 |
Description | Wellcome Trust Translational Award |
Amount | £573,461 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Translation Award |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2013 |
End | 04/2017 |
Title | Controllable Biological Signalling |
Description | The tool is currently under evaluation for IP protection. However, it is a method for enabling presentation of growth factors into a standard industry bioreactor where factors are required at far lower levels than previously reported, and where factors can be introduced and removed non-invasively. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | Provision of tool will be provided after IP protection |
Title | Supplementary information files for A quartz crystal resonator for cellular phenotyping |
Description | Supplementary files for article A quartz crystal resonator for cellular phenotyping. Cell therapy manufacturing is limited by lack of online tools capable of realtime in-process monitoring, particularly of simultaneous changes in multiple orthogonal (mutually independent) parameters. Here, we studied changes in CD36 expression, number density and size (area) of erythroblasts through different stages of erythropoiesis in vitro using a quartz crystal resonator (QCR), integrated with a microscope, |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://repository.lboro.ac.uk/articles/dataset/Supplementary_information_files_for_A_quartz_crystal... |
Description | Advanced Bioprocess Design Ltd |
Organisation | Advanced Bioprocess Design Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | The partnership is built around a novel software product developed by Advanced Bioprocess Design Ltd for dynamic mechanistic modelling of cell culture systems, particularly for manufacture design. We are the partner research group for the company and have provided software design input, user requirement feedback, and testing of model development in specific relevant processes. We are generating a co-publication strategy of modelling workflow and exemplars for manufacturing in regenerative medicine. |
Collaborator Contribution | Advanced Bioprocess Design provide extensive and free engineering and software development time input - approximately 20 days a year - for modelling support and user specified Software changes. The company also provide heavily subsidized access to the software which we use across a wide range of projects and teaching. |
Impact | Multiple evolutions of the new software tool, StemCellCAD. The collaboration is highly interdisciplinary involving cell culture biologists, bio-manufacture engineering, mathematical modelling, and software development. |
Start Year | 2016 |
Description | Advanced Bioprocess Services |
Organisation | Advanced Bioprocess Services Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have partnered with Advanced Bioprocess Services to deliver technology and process development expertise to clinical stage therapeutic product companies. These have included pre-clinical bioreactor process development and modelling for several Boston (US) based blood products companies, and process development for leading UK based companies in neural stem cell and immunotherapies. Our contribution has been specifically in novel process model development, novel methods to improve process efficiency, and technology design. |
Collaborator Contribution | Advanced Bioprocess Services manage the interface with companies seeking process development and provide extensive high value reagents and consumables for project work, either directly or via other collaborating companies, as well as providing access to the most relevant and protected industrial processes for development of our research. Since 2016 Advanced Bioprocess Services have directly funded 258,000 GBP of research and impact activity through the University as of end of 2019 |
Impact | Novel industrially applied processes |
Start Year | 2016 |
Description | Megakaryocyte Culture for Platelet production |
Organisation | University of Cambridge |
Department | Department of Haematology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are taking a novel cell type (as described below) and culturing in a scalable production system. We are applying a novel software based modelling approach to define optimal process operation. |
Collaborator Contribution | Our partners have produced genetically modified megakaryocytes that can proliferate in a relatively stable form over a long period. They have generated cell stocks for us, transferred analytical protocols and provided training, and provided scientific and technical advice. |
Impact | Data on megakaryocyte growth dynamics and influences; outputs in preperation |
Start Year | 2015 |
Description | Scottish National Blood Transfusion Service (Manufactured Blood Clinical Trial Development) |
Organisation | NHS National Services Scotland (NSS) |
Department | Scottish National Blood Transfusion Service |
Country | United Kingdom |
Sector | Public |
PI Contribution | Generating proof of concept data regarding scaled manufacturing of red blood cells to enable subsequent application for a full Wellcome Trust Translational Award |
Collaborator Contribution | Providing the laboratory based process to use in the scaled system, and providing cells and reagents at the appropriate point of differentiation to be compatible with the scalable manufacturing systems. |
Impact | Multidisciplinary; Cell biology, Clinical Haematology, Process Engineering, Manufacturing Engineering Main impact was the generation of data required to successfully bid for Wellcome Trust Translational Award (reported under separate section) |
Start Year | 2013 |
Title | StemCellCAD |
Description | This is a software package that allows conceptual description and linking of the dynamics of species in a system. It is tailored for advanced cell human cell cultures so includes common behaviours such as growth, decay, promotion, inhibition amongst others and enables specification of common arising dynamic phenomena such as feedback loops. The software allows data fitting to described models and sensitivity analysis. |
Type Of Technology | Software |
Year Produced | 2016 |
Impact | The software product was developed in collaboration with Advanced Bioprocess Design Ltd. ABD developed the software to meet our modelling requirements and supported us through multiple case studies. The software is now being applied in a range of academic and industrial programmes to generate models of a range of culture systems; this has defined further experimental work and identified mechanistic behaviours and operational risks. Outputs in preparation. |
Company Name | SAFI BIOSOLUTIONS UK LIMITED |
Description | As the cell therapy commercialization partner of a 5-year Department of Defense program to manufacture on-demand blood products, Safi Biosolutions and its collaborators are working to 'crack the code' of Cell Therapy 2.0 challenges of manufacturing at appropriate scale, high consistency of product, and economically viable cost of goods by integrating world-leading expertise in cord blood stem cell expansion, bioprocessing optimization, manufacturing scale-up and cryostorage. Lead development programs for manufactured, on-demand cell therapy products include red blood cells for trauma, tailored red blood cells for specific transfusions (e.g. sickle cell disease) and a neutrophil progenitor cell therapy for the treatment of chemotherapy-induced neutropenia. |
Year Established | 2021 |
Impact | Established an economic manufacturing platform for therapeutic blood products |
Website | https://safi.bio/ |
Company Name | ADVANCED BIOPROCESS SERVICES LIMITED |
Description | Bioprocess Development Service Provider for Cell and Gene Therapies |
Year Established | 2016 |
Impact | Worked with a range of early stage cell and gene therapy companies to deliver novel, economic, and robust manufacturing processes for pre-clinical models; provided the development services that have directly supported in excess of $20M of private raise. |