Cellesce, together with peptide 3D scaffold specialists, Manchester BIOGEL, and complex protein manufacturer, Qkine, have been awarded Innovate UK Sustainable Innovation Funding to develop fully synthetic, chemically-defined three-dimensional (3D) scaffolds that mimic more accurately the physiological environment in the human body and enable manufacture, scale up and improved reproducibility of patient-derived organoids.

Organoids are three-dimensional (3D) structures derived from stem cells that mimic mammalian organs. These have transformative potential as new platforms for faster drug discovery and better model systems for determining drug efficacy and toxicity. As well as pushing forwards basic biological understanding by more accurately replicating the responses seen in humans and reducing the need for animal use in research. However, existing methods for growing organoids rely predominantly on a 3D growth matrix extracted from mouse tumours to provide a supporting structure, this material is complex and poorly defined, leading to challenges with scale-up and limiting use in drug discovery platforms and other research applications.

This project seeks to address these issues by combining the existing technologies of Manchester BIOGEL’s tuneable peptide hydrogel scaffolds with Qkine’s optimised high purity growth factors to build a new 3D cell culture scaffold that will mimic the natural environment of the body. Importantly, all the components will be chemically-defined and animal product free, enabling greater experimental reproducibility. Working together with the leaders in patient-derived organoid scale-up, Cellesce, they will develop and tailor these new materials for scalable and reproducible organoid culture.

Commenting on the grant award, Professor Aline Miller, CEO of Manchester BIOGEL said “I am very excited about this project – not only will we establish a new collaborative consortium, but we will also bring together our significant expertise to contribute to the development of an enabling platform technology with pressing scientific need, and with strong commercial potential.”

A successful outcome from the collaboration will lead to the development of improved human cell-based models. This addresses key scientific challenges in the stem cell and drug discovery sector, reduces animal use in research, and strengthens UK life science manufacturing to provide a long-term sustainable return on investment for UK PLC.

colorectal cancer organoids

Colorectal cancer organoids ©National Physical Laboratory

About Manchester BIOGEL
Manchester BIOGEL is a global leader in the design and manufacture of synthetic self-assembling peptide hydrogels that provide a natural physiological extracellular matrix to support long term culture. Their biologically relevant hydrogels mimic the cell micro-environment and their stiffness and functionality can be modulated to simulate the natural environment of all human tissues. Manchester BIOGEL’s proprietary technology is 100% ethical, animal free and chemically defined. It opens up opportunities and offers clinically translatable solutions to meet current healthcare challenges within the growing fields of 3D cell culture, 3D bioprinting, tissue regeneration and drug discovery.

manchesterbiogel.com

About Qkine
Qkine is a Cambridge, UK-based manufacturer of high purity, animal-free growth factors, cytokines and other complex proteins. Qkine combines proprietary production processes with protein engineering technology to tackle fundamental biological and scale-up challenges for the fast-growing stem cell, organoid, regenerative medicine and cultured meat sectors.

qkine.com

We recently announced the impending arrival of new patient-derived Breast Cancer organoid lines. These new lines have been fully validated for compatibility with our proprietary organoid expansion process. We have recently published a new Application Note which describes the process and demonstrates the stability of breast cancer organoid phenotype, genotype and drug response following bioreactor expansion.

manual v bioreactor organoid expansion

Excitingly, our bioreactor-expanded organoids demonstrate reduced variability and greater batch-to-batch reproducibility than their manually grown counterparts in drug response assays, thus reinforcing their compatibility with drug screening applications. Go to the App Note.

Breast cancer is one of the most common types of cancer. Cellesce has invented and patented a unique bioprocess for the expansion of human-derived, cancer organoids for applications in cancer drug discovery and in collaboration with Cardiff University, is finalising the development of a range of breast cancer organoid lines. These will be available off-the-shelf towards the end of 2020.

Cellesce’s organoid expansion technologies minimise manual handling time and maximise reproducibility, to position organoid technology as a cost-effective and accurate tool in early-stage drug discovery.

Organoid drug assay workflow

A number of new and unique breast cancer organoid lines representing the key molecular subtypes of breast cancer have been established from primary patient biopsies or from Patient-Derived Xenograft (PDX) tissue.

The organoid lines have never been cultured in 2D adherent conditions, and faithfully represent the tumour from which they were derived.

Breast cancer organoids expanded at scale by Cellesce have been shown in pilot studies to generate more reproducible data than their manually grown counterparts, while maintaining the phenotype and genotype of the starting tissue.

Find out more.

A new paper exploring the application of patient-derived organoids (PDOs) in the study of novel inhibitors of stem cell activity has recently been published in the journal PLOS ONE (Badder et al., 2020).

The study utilised 3D image-based morphometric analysis to quantify over 600 different features from individual organoids following treatment with TNKSi. While the morphometric analysis approach mirrored the trend seen in traditional biochemical assays, importantly this more sophisticated method was able to detect subtle alterations in growth and morphology in response to TNKSi with much greater accuracy. This leads to the conclusion that whilst traditional biochemical assays still have value in detecting compounds that merit further investigation in early stage drug discovery, combining these with 3D morphological analysis could be the key to unlocking the full potential of organoids in predictive drug testing at a much larger scale.

The study was led by Cellesce founding director Professor Trevor Dale’s Cardiff University-based academic research group working together with Cellesce and other partners. It describes the derivation of a novel set of colorectal cancer PDOs. The PDO models are then used as a platform to test the response of colorectal cancer to Wnt pathway modulation using small molecule inhibitors of the tankyrase protein (TNKSi). The work utilises a range of analysis techniques and highlights 3D quantitative image analysis in particular as having the potential to greatly enhance the high throughput prediction of compound efficacy in pre-clinical testing.

In recent years, there has been a shift within the drug discovery industry to focus on the development of compounds targeting ‘cancer stem cell’ populations within tumours. Historically, conventional chemotherapeutics have aimed to target the tumour bulk, to kill as many tumour cells as possible; the effects of which are usually to drive tumour regression in the short-term, albeit with greater side-effects – and a high chance of patient relapse. It is now widely understood that, in order to permanently prevent tumour growth, the initiating cancer stem cell population must be removed or inhibited. In the patient, this might have a relatively small impact initially on overall tumour size, but a longer term more effective treatment caused not by killing the cells, but by a more subtle change in the behaviour of the cells within the tumour.

The study of such targeted compounds has led to demand for better predictive model systems. While historical drug discovery has relied heavily on the predictive power of 2D cancer cell lines, their lack of cellular heterogeneity and relevant phenotypic behaviour leaves them largely unsuited for the study of cancer stem cell inhibitors, and far from ideally placed for anti-cancer drug development in general.

PDOs – which retain intra-tumoral complexity and, crucially, stem cell function – are now gaining increasing momentum as predictive in vitro models in the drug discovery field, with the potential to reduce compound attrition rates and development costs, ultimately increasing the number of successful compounds available for use in the clinic. A more complex model, the study argues, demands a more comprehensive method of analysis that is capable of capturing the complete range of changes that may occur in response to treatment.

The organoid lines generated for this study are licensed for sale by Cellesce in large scale validated batches produced using Cellesce’s patented bioprocess. Cellesce PDOs:

  • Are vialled ready for plating straight into the desired format
  • Come with full protocols and technical support
  • A custom expansion service is available with:
    • Culture optimisation and banking options
    • Large scale expansion with custom vialling

Cellesce has produced an Application Note that summarises the paper’s findings.

Novel targeted drugs are already bringing significant benefits to many cancer patients. However, the costs of administering these new treatments often precludes their widespread use in routine clinical practice. The international pharmaceutical industry continues to defend these high prices by emphasising their need to compensate for the high attrition rate of promising new compounds through the drug discovery process and into clinical development.

Early decisions on compound selection are often made by using conventional monolayer or suspension cultures of cancer cell lines, which can be poorly predictive of the relevant therapeutic effects subsequently observed on a patient’s tumour in the clinic. As a result, many apparently attractive new drugs that elicit positive data early on in cell-based assays or xenograft animal models then fail to deliver meaningful endpoints in clinical trials.

3D Organoid Technology

Tumour-derived organoid lines grown in vitro from patient biopsies are a novel solution to this problem, as they have the potential to be more predictive earlier in discovery and thus reduce the high rate of compound attrition in downstream development. Bioprocessing technologies for the industrial expansion of organoids are now emerging to overcome this problem. This review analyses the challenges and solutions required to exploit human cancer organoids to meet the growing demand for their practical application in drug discovery.

By reducing the high rate of attrition of compounds in drug discovery, it is expected that the cost of new cancer treatments can be reduced and, therefore, made more widely available across the world. The future economic and medical benefits of this new approach, along with some consideration of the resultant carbon footprint of cancer drug discovery are also discussed.

View and download the paper here.

An article which appeared in the Financial Times of 9th December, ‘Organoid Innovation Offers Potential for Cancer Research,’ highlights the increasing use by Pharmaceutical companies of organoids derived from specific tumours to screen potential cancer drugs.

The article tracks the history of organoids, the creation of the Hubrecht Organoid Technology [HUB], and mentions the role that Cellesce is playing in the scale up in the production of organoids for Cancer Research.

One of Hub’s collaborating companies in the UK is Cellesce, spun out of Bath and Cardiff universities and based in Cardiff. Its technology scales up the production of organoids, initially mainly for cancer research.

“Until now growing organoids has been a laborious manual process with considerable variability between batches, carried out mainly by specialist research labs,” says Mark Treherne, Cellesce chief executive. “We have built a scalable process that can be used in applications requiring large numbers of organoids.”

Cellesce started with colorectal cancer and is moving on to produce breast, lung and other mini-tumours, derived with consent from individual patients with known medical histories. “We have a dozen customers so far,” Mr Treherne says. “Some are using them to screen novel anticancer compounds and some for genetic studies.”

 

Cellesce, in partnership with the Inherited Tumour Syndromes Research Group at Cardiff University, has won support for further organoid research from the Accelerate programme through the programme’s Clinical Innovation Accelerator (CIA). Accelerate is a pioneering collaboration between Welsh universities and the Life Sciences Hub Wales. Working with industry, it helps translate innovative ideas into new technology, products, and services for the health and care sector. The Accelerate programme is supported by the Welsh Government and the European Regional Development Fund. This research will focus on establishing an organoid based model for the pre-clinical testing of drugs for Familial Adenomatous Polyposis (FAP) and MUTYH-associated polyposis (MAP) patients.

Cellesce has developed unique bioprocessing technology for growing organoids at the scale and with the consistency required for multiple cancer drug discovery applications. Organoids are adult stem cell-derived, 3-dimensional replicas of patients’ tissue grown in the laboratory. By using organoids in drug discovery screening assays, scientists can identify active compounds for further progression, earlier in the drug discovery process, weeding-out less attractive compounds before incurring higher downstream costs.

FAP and MAP are genetic syndromes which predispose patients to a near-100% lifetime risk of colorectal cancer. This project aims to establish a pre-clinical organoid model of the syndromes, in vitro, to target the drivers of the disease. Cellesce will be working with Laura Thomas and her team, who are based in the Cardiff University Cancer Genetics building at the University Hospital of Wales, Heath Park. The aim is to derive organoids from tissue donated by patients with FAP and MAP and grow them at scale. These intestinal organoids will contain all the different cell types found in the original organ and recreate the spatial organisation of the original tissue. They will be used as pre-clinical models of intestinal tumour initiation in order to identify the genetic mechanisms of the disease, to test potential drugs for the treatment of FAP and MAP and for developing therapeutic strategies for the prevention of inherited and sporadic intestinal cancers. These organoid models will complement Cellesce’s existing range of colorectal cancer organoids, providing models at both early and late stages of intestinal cancer development.

With support from CIA, the academic team, led by Professor Julian Sampson, will bring in their expertise of biology/medicine, genomics and bioinformatics, and experience in governance and accreditation under the Human Tissue Act (HTA). This will be complemented by Cellesce’s scientific knowledge, experience in organoid culture, bioengineering technology and expertise in the expansion of organoids. The project will also benefit from the project team’s links with the NHS including access to donated patient tissue through the Wales Cancer Bank and support from geneticists, gastroenterologists and surgeons.

“The Accelerate support won with Cellesce enables the Cardiff University Inherited Tumour Syndrome Research Group to build upon its track record of genetic discovery research and translation of its findings to pre-clinical and clinical trials of novel targeted treatment,” said Professor Julian Sampson. “This presents a fantastic opportunity to improve care for patients with inherited tumour syndromes and to further develop innovation in precision medicine in Wales.”

“This project aligns well with the Accelerate aims by combining academic expertise with pioneering commercial research and innovation in a common enterprise,” commented Dr Mark Treherne, Cellesce’s Chief Executive. “Not only do we collectively expect to improve patient outcomes but also build on the notable place of organoids in drug discovery for cancer.”

 

European Regional Development Fund

 

About Accelerate
The Accelerate programme, is a collaboration between Life Sciences Hub Wales, Cardiff University, Swansea University, and the University of Wales Trinity Saint David. It offers enterprises bespoke innovation expertise to refine and validate their health care solutions and speed up their adoption into the health sector in Wales for economic benefit.

Accelerate is a dynamic, engaging programme which operates strategically. It is here to support opportunities to flourish and grow, guiding and navigating innovators, refining an idea to become a robust business model.

Accelerate provides a tailor-made, bespoke suite of support and applies it to each individual concept to provide innovative solutions, giving each idea the best possible opportunity for success.

Accelerate is co-funded by the European Regional Development Fund.

To find out more, please go here.

Cellesce has been successful in winning support for three core organoid research projects via the KESS (Knowledge Economy Skills Scholarships) 2 Programme. These KESS 2 research projects are carried out through work done by a dedicated student at PhD level, supervised by an academic team at Cardiff University who work in partnership with Cellesce. KESS 2 is a pan-Wales higher level skills initiative led by Bangor University on behalf of the higher education sector in Wales. It is part-funded by the Welsh Government’s European Social Fund (ESF).

Cellesce has developed unique bioprocessing technology for growing organoids at the scale and with the consistency required for multiple cancer drug discovery applications. Organoids are adult stem cell-derived, 3-dimensional replicas of patients’ tissue grown in the laboratory. By using organoids in drug discovery screening assays, scientists can identify active compounds for further progression earlier in the drug discovery process and can weed-out less attractive compounds before incurring higher downstream costs. Cellesce’s strategy is to work with key research laboratories to develop the next generation of organoid biology for commercial exploitation worldwide. In parallel, these projects also allow the Company to help generate and train the next generation of scientific talent in a commercial setting.

These KESS 2 research projects provide an interesting insight into the direction of Cellesce’s organoid technology research. The first project is to be conducted within Cardiff University’s Schools of Mathematics and Biosciences and focuses on improving the understanding of organoid formation and morphology through computational modelling of 3D image data. Using breast cancer organoids, it is hoped that changes in morphology can be linked to changes in the activity of the signalling pathways that cancer drugs are designed to target.

The second project focuses on two genetic syndromes, Familial Adenomatous Polyposis (FAP) and MUTYH-associated polyposis (MAP), which predispose patients to a near-100% lifetime risk of colorectal cancer. The project aims to create a pre-clinical organoid model of the syndromes in vitro and then use CRISPR gene editing technology to target the drivers of the disease. This project will be conducted in collaboration with Cardiff University and the Wales Gene Park.

The third project focuses on the development of Liver and Hepatocellular carcinoma (HCC)-derived organoid lines, and will be conducted in collaboration with the University’s School of Biosciences. This project aims to establish and characterise novel liver-derived organoid lines, which can be subsequently used for drug toxicity and metabolism studies, as well as to screen new anti-cancer therapies.

“The KESS 2 programme is providing a significant boost to our range of organoid disease models and imaging capabilities,” commented Dr Mark Treherne, Cellesce’s Chief Executive. “By working closely with leading researchers and post graduates at Cardiff University and collaborating with the Wales Cancer Bank, Cellesce will obtain key data to expand the breadth of the solutions that we provide to our customers and collaborative partners.”

KESS - Knowledge Economy Skills Scholarships

Knowledge Economy Skills Scholarships (KESS 2) is a pan-Wales higher level skills initiative led by Bangor University on behalf of the HE sector in Wales. It is part funded by the Welsh Government’s European Social Fund (ESF) convergence programme for West Wales and the Valleys.

Horizon Discovery™ is at the forefront of cell-based screening using 3D models and is now developing a robust and reproducible organoid-based high-throughput screening platform. Organoids reflect cell heterogeneity and mimic native histologic architectures of the originating tissue – features that are not typically seen in 2D models or spheroids. Employing this next generation of 3D microtissues can therefore provide crucial information about compound activity and might help to reduce the high failure rate of cancer drugs in clinical trials.

 

Cellesce and Hubrecht Organoid Technology (HUB) have today announced a licence agreement for the expansion of organoids using Cellesce’s own bioprocessing technology and HUB Organoid Technology for the scale up of breast organoids.

Cellesce and HUB have an ongoing agreement for the expansion of organoids using HUB Technology. In a new project, funded by Innovate UK, Cellesce will expand breast cancer organoids using a combination of HUB Organoid Technology and Cellesce’s own bioprocessing technology. The project aims to confirm that breast cancer organoids remain genetically and phenotypically stable and continue to faithfully recapitulate the characteristics of the tumours from which they were originally derived. The project will provide support for the scaling of organoid expansion to generate the quantities of organoids required by commercial and academic researchers in drug discovery programmes.

Cellesce Chief Executive, Dr Mark Treherne, commented: “By partnering with HUB Cellesce will be in a position to provide an integrated drug discovery solution. This will be a comprehensive package that supplies organoids at scale which will increase the impact that organoid models are having on the cancer research community.”

“HUB Organoid Technology will benefit from Cellesce’s innovative technology to expand large quantities of organoids such as breast cancer organoids.” added Dr Rob Vries, Managing Director of the HUB.