Public Funding for Autolus Limited

Immune cells such as T cells can be harvested from a patient's blood and genetically engineered to recognize and destroy cancer cells. This kind of immune therapy, which includes CAR T cell therapy is proving to be highly effective in treating cancers which have become resistant to chemotherapy and radiotherapy. There are currently six such engineered immune cell therapies licensed which are revolutionizing the treatment of many cancers. Many more cell therapies are under development. The greatest challenge for this treatment approach is that an individual treatment must be manufactured for each patient, which is expensive. Alternative approaches such as manufacturing "off-the-shelf" immune cells has not worked well. However, manufacturers of engineered cell therapies have developed processes that are automated, and which are much shorter. These are reducing the cost of these therapies. Standard therapeutics are manufactured and released in large batches of thousands of doses so that release testing is a small part of cost and complexity per dose. With individualized manufacture however, each patient's product requires its own release testing and product release. Notably, release testing of engineered immune cell therapies is complex and expensive. With quicker automated manufacturing, product release is now becoming a bottleneck, with release testing taking up an increasing proportion of total cost of goods. The overall aim of Speed-CELL is to make batch release cheaper and faster, but still ensure that only high-quality products get to patients. This will reduce the cost of these cell therapies. Importantly, it will reduce the waiting time for patients who often have aggressive cancers. The speed-CELL will achieve this primarily through broad engagement - we will build an expert consortium of UK academics, medical centres, industrial partners to inform and work with governmental agencies, such as regulators, to develop release testing technologies and processes which will reduce the cost and time take to release engineered cell therapy products. More specifically, Speed-CELL consortium will: \* Assess the UK cell manufacturing landscape to identify release critical bottlenecks e.g. testing for sterility and product potency. \* Identify cutting-edge analytic technologies that can be adopted to streamline and accelerate release. \* Develop digital technologies like expert systems which can automate release. \* Establish regulatory pathways to enable these methodologies and technologies. This initial funding will help lay the groundwork for this ambitious project which will act to increase competitiveness of UK academic and industrial cell therapy groups and bring these therapies faster to patients.

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Autolus are working to leverage existing expertise in antibody binder technology. We have designed a series of molecules that have the potential to lower viral load in patients, which is expected to reduce disease severity and lower the likelihood of developing symptoms that result in hospitalisation. The goal of the project is to evaluate the technical feasibility and rapid development of disease-ameliorating biological drugs.

Advanced Therapies have come of age. The spectacular clinical results demonstrated by novel gene-engineered T-cell therapies, with subsequent regulatory approvals in the US and EU, have confirmed the commercial reality of a new class of therapeutics that offer real hope to patients who are bereft of effective treatment options. But behind this hope lies a deep concern that problematical scalability will severely limit patient access to these therapies. Current Supply Chain technologies and Delivery approaches are inadequate to address the needs of complex madicines that require individual manufacture and a 'closed loop' supply chain whereby the hospital and patient themselves are both the provider of input material and the receiver of a personalised medicine. What is required is a sophisticated approach that allows for flawless tracking and tracing of each batch both during manufacture and during delivery. Integratred into this supply chain is a series of intelligent systems that manage all aspects of manufacture, thus permitting the efficient and scalable certification and release of thousands of batches without any compromise to Product Quality. This Project will pilot these technologies at scale and integrate those findings into a full scale UK-based Advanced Therapies Manufacuring Centre. Keywords: Advanced Therapies; Personalised Medicines

"**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."

"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."

"Advanced Therapies have come of age. The spectacular clinical results demonstrated by novel gene-engineered T-cell therapies, with subsequent regulatory approvals in the US, have confirmed the commercial reality of a new class of therapeutics that offer real hope to patients who are bereft of effective treatment options. But behind this hope lies a deep concern that high cost-of-goods and problematical scalability will severely limit patient access to these therapies. A critical component of these therapies is a recombinant viral vector capable of effectively transducing the T-cells and enabling the expression of novel anti-tumour receptors. Unfortunately, the current technologies to manufacture these vectors at commercial scales are not fit for purpose. This project will combine leading academic expertise and the commercial imperative of a UK Biotech company to create innovative and scalable viral vector processes that will facilitate patient access to Advanced Therapies."

Chimeric Antigen Receptor therapies (CAR-T), represent an entirely new, potentially transformative approach to treating cancer. They combine the precision of a monoclonal antibody with the potency and persistence of the human immune system. Researchers in the USA have recently reported clinical data using CAR-T in blood cancers which are causing great excitement within the medical community. High response rates are being achieved even in those patients who have proved refractory to previous treatments. Autolus, a UK spin-out company from UCL, has proprietary technology which could broaden the application of CAR-T therapies beyond liquid cancers and into common, solid tumour types. However, CAR-T products are complex, personalised advanced therapy medicines (ATMPs) and consequently require a correspondingly complex manufacturing process. For these pioneering therapies to become viable, accessible medicines; there will need to be innovation in the manufacturing technology. The project will combine leading UK expertise to develop and demonstrate a scalable, commercially-viable manufacturing process for CAR-T therapies.

T-cells are immune cells in our bodies whose function is to "seek and destroy" cells which are infected by viruses. Since T-cells actively move around our bodies looking for infected cells, medical science has long tried to make these T-cells attack cancer cells. Because cancer cells usually come from normal cells in our bodies without virus infections, T-cells don't normally attack them. By taking T-cells from a blood sample and "re- programming" them using genetic engineering, medical science has found a way of using T-cells to attack cancer. These engineered T-cells are called "CAR T-cells" and they can be given back to the patient as a drip. Once back in the patient, they "seek and destroy" cancer cells as if they were virus-infected cells. CAR T-cells seem to be a very effective new form of cancer treatment. Cancers can come from any cells in our bodies. Even T-cells can become cancer cells and some of these cancers are called T-cell lymphomas. This project deals with the particular problem of CAR T-cells attacking T-cell lymphomas. Scientists working on this project have found a way of making CAR T-cells that attack the cancerous T-cells but leave plenty of normal healthy T-cells alone.

Multiple Myeloma (MM) is a cancer of a type of white blood cell called a plasma cell. MM is a disease of older people. Patients with MM develop bone fractures, pain, infections and kidney failure due to this cancer. Although it can be controled for a period, MM is currently incurable. T-cells are the part of our immune system which directly kill infected cells. They can be easily taken from a blood sample and grown in the laboratory. Using genetic engineering tools, these T-cells can be “re-programmed” so that a patient’s own T-cells recognize and kill cancer cells. This can be achieved by introducing a gene for an artificial protein called a chimeric antigen receptor, or CAR for short, into a patient’s T-cells. While T-cells normally ignore cancer cells, with this modification they attack cancer cells with the same vigour and determination as they would naturally attack virus infections. Recent clinical data leave little doubt that CAR T-cell therapy will be game-changer in cancer therapy. We have developed a CAR which targets MM cells and with this proposal plan to test the effectiveness of a patient's own T-cells engineered with this CAR.