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bLadder cAncer URine cEll aNalysis

Periodic Reporting for period 3 - LAUREN (bLadder cAncer URine cEll aNalysis)

Reporting period: 2017-06-01 to 2018-07-31

Bladder cancer is a common cancer, with over 429,000 new cases diagnosed globally in 2012, and it is an expensive cancer, costing the UK alone over £50 million per year. Currently, the gold standard diagnosis and management tool for bladder cancer is cystoscopy, which is expensive, uncomfortable and carries a risk of infection. Because of the high recurrence rate of bladder cancer (up to 35% in the first 3 years), these shortcomings are exacerbated by the need for repeated surveillance, which may extend to quarterly cystoscopies for 1-2 years post-surgery, every 6 months in year 3-4, and annually thereafter.

By transforming urine cytology, a complementary adjunct to cystoscopy, Cytosystems is developing technology to reduce the number of cystoscopies required for bladder cancer patients. The monoclonal antibody at the core of Cytosystems' assay is specific for minichromosome maintenance protein-2 (MCM2), licensed by Cancer Research Technology. Enabling technologies have been developed to create an integrated bladder cancer risk stratification package BladderLightTM. The three components of BladderLightTM are as follows, which correlate as the three aims of the project:

• A low-cost, single-use cell collection device which both preserves cells and optimises the quality of cell capture

• Patented MCM2 biomarker technology stain

• Digital imaging and diagnostic algorithms. The automated analysis highlights cancer cells for clinical viewing.

The first objective of the project is to design, evaluate, and manufacture pre-prototype devices, in conjunction with a specialist medical device design company. These devices will be subject to full clinical evaluation for regulatory purposes. Our results to date have been equivalent to the cell capture of centrifugation – the laboratory ‘gold’ standard. The final prototype will then be subject to a larger trial in 2017 as part of the full BladderLightTM package.

The second project objective is to define the procedure of slide preparation and staining. Several optimisation experiments have been informed in-house and renowned consultant cytopathologists have advised. Such slide preparation has paved the way for developing the automated analysis.

The third objective of the project is to analyse the images of the stained slides which has been done in collaboration with a university. The analysis concerns staining of cells with our patented proliferative biomarker MCM2, and also concerns morphometric features. The first set of results are very encouraging, proving our algorithms to have the potential to be very robust.

Underpinning the objectives of the project is the regulatory path. Before market placement and an extensive programme of clinical evaluation, Cytosystems is aiming for CE-marking and FDA approval.
Our first activity concerned the concept and planning of the project. We prepared a formal plan documented to ISO13485 (the international standard for medical devices) including planning of risk assessment and management throughout the project and validation planning - how the various stages will be validated to regulatory standards. We considered the feasibility within timescales, budgets and resources.

We reviewed our proposed cell collection method with initial focus on the method of cell capture, we were able to do this before we formally employed a sub-contractor who added mechanical design, ergonomics and manufacturability experience. Design concepts were produced and considered with manufacturing strategies. Some design concepts progressed to prototype models tested in our laboratory using urine samples, some spiked with EJ28 cancer cells but later, after ethics approval and contractual arrangements, we used urine from bladder cancer patients. We compared our cell collection method with the established technique of cell centrifugation, our results confirming that our methods are at least equivalent to or superior to centrifugation. The design has been reviewed for manufacturability and soft tooling is in progress.

We also achieved a far greater understanding than we had expected concerning cell behaviour and the challenges of separation whilst minimising the risk of cell damage, whilst this has taken longer than expected, our greater understanding allows us to secure intellectual property by patent.

We defined the procedure of slide preparation and staining, a precursor to the objective to analyse images of the slides stained with our proliferative biomarker MCM2 including morphometric features. We investigated available image processing and analysis software and have started initial discussions with a software house for commercial application. The ethics approval and contractual arrangements for urine samples from bladder cancer patients has led us to a good supply of material for proving our procedures and over 700 clinical samples have now been used to verify the analysis.

In parallel with the scientific and laboratory work we developed the documentation structure for ultimate regulatory approval both for Europe (CE-marking) and the USA (Food and Drug Adminstration – FDA). We are now getting guidance from the FDA for the appropriate regulatory route and details of addition information that the FDA requires. Regulatory routes have been agreed and we are currently in detailed planning for clinical trials.

We made progress with exploitation and dissemination (including commercialisation). We carried out a martket evaluation and developed an exploitation strategy. We are now in contact with possible collaborating companies, to engage with markets such as Germany, France, Italy, Spain, UK – in Europe – and the USA, China, Japan and India in the rest of the world. We also supported our commercialisation aims, for example, – a new website with news items and press releases, product brochure, attendance at the MEDICA trade show and collaborating with a company video.
Our work on the cell collection device highglighted some unexpected issues concerned with cell handling but has led to progress beyond the state of the art. Our work led to some novel ideas and the first patent application from the project. Our second patent application concerns the monoclonal antibodies which we use and a third patent concerning image analysis is in preparation.

Based on the project’s progress we believe that our methods and products will lead to a significant improvement in the management of patients with bladder cancer and eventually helping to diagnose bladder cancer before treatment. Details of the socio-economic impact will be forthcoming after we carry out a health economics study but already it is clear that our methods and products should be more economic thus saving direct and indirect healthcare costs and reduce the number of uncomfortable procedures for patients.
Prototype cell collection device for laboratory use