Public Funding for Asymptote Limited

"**Advance Therapy Medicinal Products (ATMPs)** **are a new generation of treatments which use patients' cells as 'drugs' to treat a variety of diseases.** Although encouraging results have been reported, this technology is complex, expensive and currently only available to small numbers of patients. In **2018** the **UK** have formed **a network of three Advanced Therapy Treatment Centres (ATTCs)** supported by the **Cell & Gene Therapy Catapult**. The ATTC network have partners made up of: ATMP developers & manufacturers, National Blood Services, Hospitals, Universities, logistics providers, raw materials suppliers & technology providers. This project is being led by the **iMATCH ATTC** (innovate Manchester Advanced Therapy Centre Hub) but involves collaboration with the other 2 ATTCs Midlands & Wales ATTC and Northern Alliance ATTC and introduces a new partner (Guy's & St Thomas's Hospital, London) to expand activities outside the ATTCs. This **Project** ""**SAMPLE**"" will harnesses a group of collaborators who share a vision of working more efficiently together so we can develop a standardised approach to the collection of tissue & cell based starting materials essential to the manufacture of Advanced Therapy Medicinal Products. Ultimately, making improvements enabling more life changing treatments to be provided to children and adults with cancer and non-cancer diseases. This project unites experts from Scotland, England & Wales: NHS Blood & Transplant, SNBTS, The Christie NHS Foundation Trust, Manchester University NHS Foundation Trust, The Newcastle upon Tyne Hospitals NHS Foundation Trust and 4 businesses with specific expertise in different aspects of delivering Advanced Therapies. The 4 commercial partners are; Asymptote, Autolus, Cellular Therapeutics & TrakCel as well as 3 non-funded participation from global medicine manufacturers and technology providers: Novartis, Gilead & Terumo BCT. We are going to focus on: coordinating patient cell collection, processing and storage of those cells and enabling efficient systems to collect **SAMPLES** from the patient or donor and so streamlining the manufacture and enabling an increase in the number of patients being treated. The UK is a world leader in these types of treatments and this investment by Innovate UK will build on these innovative therapies and technologies thereby improving the lives of the UK population but also making the UK a destination for both investment and also other non-UK developed therapies in both trials and ultimately standard therapies."

"Advance Therapies are a new generation of treatments which use patients' cells as 'drug' to treat a variety of diseases. Although encouraging results have been reported, this technology is complex, expensive and currently only available to small numbers of patients. We have formed the Innovate Manchester Advanced Therapy Centre Hub (iMATCH); this is a group of collaborators who share a vision of working more efficiently together so we can offer Advanced Therapies to more children and adult patients with cancer and non-cancer diseases. iMATCH unites experts from The Christie NHS Foundation Trust and Manchester University NHS Foundation Trust, The University of Manchester and 9 businesses with specific expertise in different aspects of delivering Advanced Therapies. Our 9 commercial partners are; Cellular Therapeutics, Aptusclinical, Chaucer, Datatrial, Formedix, Asymptote, AstraZeneca, Agenus and The Christie Pathology Partnership. iMATCH will resolve the challenges and expand facilities to allow us to design and run larger clinical trials so that we can to treat greater numbers of patients within the NHS, safely and efficiently. We are going to focus on; * Coordinating patient cell collection * Processing and storage of those cells * Developing efficient systems to track samples from the patient, through manufacture and back to the patient * Ensure we have all the information we need, from each patient we treat, to know whether a clinical trial has been a success; this will include long term follow-up of patients These clinical trials are complex and challenging to run; it is important that we provide specific education for our doctors, nurses and the teams that support them. We want to define the education packages needed then offer this training to all Manchester-based partners, then any national and international teams. This will increase the use of Advanced Therapies world-wide. Manchester is an excellent choice for this investment by Innovate UK; we have a large population of 3.2 million people, two substantial hospital sites with existing experience offering these treatments to a variety of patients, a devolved Health Care System and an ability to draw together companies who can help us to overcome the complex challenges. Together we will improve patient outcomes."

"The Northern Alliance Advanced Therapies Treatment Centre (NAATTC) is a group of NHS hospitals and services. NAATTC has a wide geographical reach across Scotland and the North of England and is responsible for the health care of 15 million NHS patients. Advanced therapies are becoming increasingly available with a growing number of companies developing them both in the UK and worldwide. They are based on the administration of gene- and cell-based products in specialities such as haematology, autoimmunity, hepatology, cardiology and ophthalmology. They are thought to be more effective than existing treatments and provide treatments for diseases where currently no effective therapy exists. However most are still in clinical trials. Advanced therapies present significant challenges to healthcare providers compared with existing treatments. Addressing these challenges in the NHS will require development and dissemination of new skills for nurses, doctors, hospital pharmacists, NHS managers, and commissioners such as NHS England and the clinical commissioning groups (CCGs). It will also require changes in the way treatment is delivered. The changes required in the NHS can only be properly implemented through partnership with the companies that are developing and providing advanced therapies to the NHS. Manufacturers will need assistance with clinical trials to ensure optimal trial design, effective recruitment into clinical trials, and long term follow up of outcomes. The manufacturing and distributing processes are complex and it is critical that these systems are integrated effectively with those within the NHS. The NAATTC already has considerable experience of delivering advanced therapies and clinical trials and will use this experience to work with manufacturers (and their supply chains) to significantly increase their capacity to deliver advanced therapies effectively, safely, and seamlessly to patients within the NHS. It will identify gaps in our existing provision and develop solutions to narrow and eliminate the gaps. It will share the best practice that it develops to other ATTCs and to other NHS organisations. The outcomes will be to deliver these promising therapies to NHS patients and to make the NHS a global leader in their delivery, creating health and wealth for the UK."

"ATMPs, which can be _cell or gene therapies_, show great potential in treating patients with conditions that cannot be cured with current treatments. These include arthritis, liver disease, several types of cancer, and diabetic ulcers. ATMPs are just beginning to be available, with the UK playing a leading role. However, even when new ATMP therapies are developed and shown to be effective, there are **major challenges in rolling them out to patients**. The reasons for this include: complexities in transporting a 'living' product, and lack of familiarity with such products in most NHS hospitals. The project lead is the Birmingham Biomedical Research Centre, a national centre of excellence. The Welsh government has also made a major investment in cell therapy and is supportive of NHS Wales as the joint-lead on this project. We are a **team of industrialists, clinicians, academics and computer system experts** who have all the necessary skills to succeed in this project. Our group **covers the Midlands and Wales** giving us access to major teaching hospitals and almost 15 million people providing a unique opportunity to set cell therapy up to succeed. We will: -Set up a network of hospitals with medical staff trained to receive and administer ATMPs. -Build seamless supply chains that ensure that 'living medicines' remain healthy and effective as they are moved from the production laboratory to the bedside. -Put in place the IT systems to manage the end-to-end process. -Validate this new infrastructure using real ATMPs -Deliver a programme that uses this infrastructure to speed up the testing of ATMPs in clinical trials. -Set-up protocols to test whether the **cost of a new ATMP is justified by its clinical effectiveness.** The benefits of MW-ATTC are (a) Patients with challenging illnesses will get access to breakthrough medicines; (b) ATMP companies will get access to the clinical mainstream and market; (c) Investment in this important industry sector will increase, as we demonstrate that the UK is an excellent location for ATMP R&D. MW-ATTC will be one of three Advanced Therapy Treatment Centres in the UK, working together for patients and ATMP innovators, to reinforce the UK's position as a world leader in this important field."

Cancer specific Adoptive T-Cell therapy (ACT) is a form of personalised medicine that harnesses the power of the patient's immune system to direct tumour-specific T-cells to kill cancer cells. The field of adoptive T-cell therapy has approached a point where the pre-clinical promise is now a clinical reality. Since the first report of use of TIL therapy in 1988, it has gone through several generations of improvement with trials using “Young TILs” unselected T cells and patient preconditioning producing excellent response rates – around 40% to 50% long term responses and around 10-20% cures. The vast potential of this field of cell therapy has been acknowledged by major pharmaceutical companies who are sponsoring multi-centre clinical trials (e.g. Novartis - CTL019, Adaptimmune/GSK - NY-ESO-1 SPEAR™). There is a market need for a robust reproducible, logistically scalable commercial process suitable for industrialisation of TIL Therapy. However, the wide-spread application of this form of cell therapy on an industrial scale is currently severely limited by the complexity associated with delivering a personalised cancer therapy. This project plans to address the major hurdles in making TIL therapy commercially viable: (i) point of collection and (ii) stabilisation of cellular material and final product.

In regenerative and transplantation medicine medicine a bottleneck limiting progress is that tissue engineered constructs cannot be manufactured on demand. Cryopreservation aims to overcome this problem, however whilst success has been achieved with cell suspensions, successful scale up of construct size has remained elusive. No methods exist that can protect complex biomasses from the severe stress they encounter during cooling and warming from liquid nitrogen (-196°C). We propose a new method, where non-Newtonian, shear- thickening fluids can be used to improve operational performance of cryopreservation. Shear thickening fluids are materials whose viscosity increases with shear stress, for example vibration. With the correct level of vibration, the material can change from a liquid to a solid instantly. We propose this as an effective material for extremely low temperature biological preservation. At the storage temperature, shear stress would be stopped as the material would remain solid (vitrified) due to the low temperatures. The shear-thickening materials make the process completely reversible.

The project brings together the technological expertise to develop a cost effective mass production and delivery a more effective biological solution to control pests with expertise in fungal cell processes and whole organism survival to ensure product long term shelf life whist retaining organism function. It combines improved product formulation with effectiveness to reduce crop losses and chemical pollution causing soil quality deterioration. The project will: Apply advanced technology to biological product development with the potential for transfer to other biological applications; Take improved laboratory knowledge to improve the cost effectiveness and efficacy to a product in the field; Develop formulations increase shelf life and confidence in the use of biological solutions to replace chemical pesticides; Produce a product appropriate for storage and use in developing economy countries; Reduce crop losses by utilisation of organisms that previously could not applied in the field

Cancer treatments are being transformed by T-Cell therapies and present a huge global opportunity. However, logistical problems transporting the cells to and from the patient are restricting the industry’s growth. There is an urgent need for a portable shipping device that combines; controlled sample freezing, temperature controlled shipping, data logging, short term frozen storage and thawing. This project will develop a basic prototype, free of liquid nitrogen, optimised for the shipping of T-cell therapies. This will be an electrically powered system based on a Stirling cryocooler, with a target isothermal hold temperature of -120°C. The system will be able to operate on mains power, a 12V vehicle supply or via an uninterruptable power supply (UPS). The storage chamber will be vacuum insulated and the device will maintain -100°C for 24 hrs when disconnected from all power. To allow transport of the source T-cells, the equipment will also be able to carry out the controlled rate freezing (CRF) of samples. The equipment will also act as a storage device at the clinical site, maintaining the sample temperature below -100°C until required for treatment. In discussions with a range of end users (academic and commercial) we have confirmed that there is currently no suitable cryogenic service for autologous treatments which can offer CRF of the source cells, temperature controlled transport, data logging, short term storage and thawing.

This application relates to the development of the consumables and associated equipment to allow the widespread clinical delivery of a bioartificial liver (BAL). Since the liver is one of the few organs that can repair and regenerate, therapies enabling regenerative medicine, that is creating living functional tissues to repair or replace organ function lost due to damage, are expected to play a role in several areas of liver disease. A bioartificial liver machine can temporarily replace the functions of the liver, allowing the damaged liver to regenerate whilst protecting the patient’s other organs from the life-threatening damage that ensues during liver failure. If the toxicity can be mitigated, within 24 to 48 hours, the majority of liver cells will enter DNA synthesis, closely followed by mitosis enabling the liver to regenerate, restoring full function within a few days.

The objective of this project is to examine the feasibility of employing fluorescent proteins as a visual means of monitoring the glass transition (Tg) of the solutions in which stem cells are stored and transported as they pass through the cold chain. The Tg of such solutions is the single most critical determinant of patient safety: at temperatures higher than Tg, diffusion and chemical reactions will quickly result in a dangerous loss of function. In this project, we will undertake a series of experiments designed to closely callibrate the light emission levels of a particular class of fluorescent proteins with the viability of a number of well-characterized stem cells such that a loss of colour can be shown to be a reliable indicator of Tg.

The project will develop a consistent, highly functional and biologically robust technology for the cryopreservation of cells in microtitre plates. These cells will be used in subsequent screening applications, for example drug safety testing. Many cell types are used for screening applications, with hepatocytes being widely used to investigate drug safety and metabolism in pharmaceutical research. Microtitre plates are used for screening; these plates have either 96 wells (200 µL per well) or 384 wells (25 µL per well). However, with the exception of robust cell types, cryopreservation of cells in microtitre plates is unsatisfactory. A high quality frozen poduct would be disruptive, lowering shipping costs considerably and giving greater flexibility to end users.

In this project we propose to develop a portable, self charging , cryogenic vessel for the shipment and short term storage of frozen material. In particular, live vaccines for use in third world. Examples of the material include live attenuated vaccines in development for treatment of human malaria and leshmaniasis as well as several veterinary products. In 3rd world applications it has been estimated that up to 50% of vaccines are discarded because of real or percived thermal damage due to failure of the cold chain. We are proposing a new concept in cold chain equipment which would eliminate these distribution issues.

Freeze drying is a method used for the stabilisation of a range of medical products, it has been estimated that over 50% of current medical products are freeze-dried due to their instability in the liquid state. However there exist a range of recalcitrant materials which cannot be satisfactorily freeze dried using conventional technology. In this project we will determine the benefits of a new method of freeze drying. The benefits of this technology could range from an improvement in the quality of materials which can currently be freeze dried (enzymes, protein therapeutics) to the creation of new products, for example freeze dried stem cells for application in regenerative medicine

Cryopreservation is a method for the long term stabilisation of biological materials for use in medicine and science. However during cooling ice nucleation is an unpredictable process and samples are observed to nucleate over a wide range of temperature. It is known that when cryopreserving cells, induced ice nucleation is highly desirable to retain functionality of cells on thawing. This project will examine the feasibility of developing an ice nucleating coating for the inside of vessels used for cryopreservation which will overcome the problems caused by random ice nucleation and improve cell recovery on thawing. This technolgy also has potential application in the freeze drying of pharmaceuticals and in food freezing.

Awaiting Public Project Summary

Asymptote Ltd is proposing to develop the first GMP compliant cryogenic cold chain for the clinical delivery of regenerative medicine therapeutics. This project focuses on the key elements of the cold chain: controlled rate freezing of large volumes, short and long term frozen storage, and controlled thawing of large volumes. Cryopreservation of cells with high functionality on thawing is essential for cost effective cell production and geographically widespread clinical treatments, and this depends on accurate control of the freezing and thawing. This project will use Stirling cryocooler technology which has unique control ability and is able to meet the GMP requirement of regenerative medicine. It is intended to produce demonstrators for the key elements of the cold chain in collaboration with four centres developing different cell therapies.

The project is to develop a freeze-thaw treatment to disable the biological 'engine' (the mitochondrion) of all the cells in a piece of fruit. The cells lose their ability to respire and, because of the resulting lack of available energy to drive the decaying processes, the fruit tissue does not decay and the nutritional shelf-life is increased. The initial target is the extension of nutritional shelf life of prepared fruit and mixed fruit salads. This is a highly innovative concept: to inflict a sub-lethal “invisible” cellular injury in order to benefit from the resulting extended nutritional life.

Awaiting Public Summary

Awaiting Public Summary