CELL, GENE and REGENERATIVE THERAPIES at UCL and NHS PARTNER TRUSTS World Leaders in the Translation of Advanced Therapies

CELL, GENE AND REGENERATIVE THERAPIES AT UCL AND NHS PARTNER TRUSTS World leaders in the translation of advanced therapies

Great Ormond Street Moorfields University College Royal Free London Hospital for Children Eye Hospital London Hospitals NHS Foundation Trust NHS Foundation Trust NHS Foundation Trust NHS Foundation Trust 2

CONTENTS

1. PREFACE 3

2. DELIVERING THE PROMISE OF CELL, 4 GENE AND REGENERATIVE THERAPIES

3. OUR COLLECTIVE CAPABILITIES: 6

• Translational Expertise 7

• Advanced Therapies Portfolio 8

• Manufacturing 10

• Commercialisation 11

• Partnerships 12

• Public and Patient Involvement 13

• Training the next generation – addressing the skills gap 14

4. CLINICAL CASE STUDIES:

• Gene-Modified Cell Therapy for Rare Disease 15

• T-Cell Engineering 16

• AAV Gene Therapy 17

• Cell Therapies 18

• Tissue Engineering and Biomaterials 19

5. REFERENCES, INTERESTING LINKS & CONTACT DETAILS 20 3

PREFACE: FEBRUARY 2018

We live in tremendously exciting times, with scientific breakthroughs Our strength in cell, gene and regenerative seemingly reported on a near daily basis. One breakthrough area therapies has been underpinned by over 30 years of research supported by research poised to deliver is the field of cell, gene and regenerative (advanced) councils, the National Institute for Health therapies. The first FDA approval for a CAR T-cell therapy to treat Research, charities, government as well as children and young adults with B-cell acute lymphoblastic leukaemia by industry. This has enabled a community was made in August 2017. Many more advanced therapy products are of in excess of 100 world class scientists at UCL to deliver on the promise of what is only undergoing the transition from pre-clinical promise to clinical reality, now being recognised as the third pillar of offering the unprecedented potential for long-term management pharmaceutical therapeutics. and even cure of disease. In the UK, the 2016 Advanced Therapies We strongly believe that the advanced therapies Manufacturing Taskforce Report recognised that “The UK has the hold the promise to transform healthcare for opportunity to secure its position as a global hub for researching, patients with some of the most severe and developing, manufacturing and adopting advanced therapies”1. The debilitating conditions, and that to do this requires partnership. Building partnerships academic sector, as exemplified by University College London (UCL), is at the heart of UCL’s ethos of excellence, our NIHR Biomedical Research Centres (BRCs) and partner NHS Trust inclusivity and global outreach, values that are hospitals, is playing a pivotal role in advancing the field. key to UCL’s strategy for the next 20 years (UCL 2034). Success will only come if we put UCL in partnership with our three NIHR Highlights in recent years include: the patient at the centre of all that we are trying BRCs at University College London Hospital Europe’s largest translational programme of to achieve. This central philosophy is one we (UCLH), Great Ormond Street Hospital for CAR-T cell therapy in adults and children share with all our partners. Children (GOSH) and Moorfields Eye Hospital (MEH) are world leaders in: First-in-human (FIH) gene therapy for rare If this is your philosophy we invite you to disease rolling out from children to adults partner with us to deliver on the promise to the the development and delivery to (Wiskott Aldrich Syndrome, ADA-SCID) patient in this fast-moving and highly exciting patients of novel cell, gene and area, as we cannot do this alone. regenerative therapies FIH gene-edited T-cells for acute leukaemia

meeting the challenges associated FIH embryonic stem cell-derived cell with manufacture therapy for macular degeneration

contributing to the training of the next Five therapy and two technology generation of scientists in the field spinout companies with a total investment of over £295 million

Professor David Lomas, Vice Provost of Health University College London Professor Marcel Levi, Chief Executive University College London Hospital Dr Peter Steer, Chief Executive Great Ormond Street Hospital David Probert, Chief Executive Moorfields Hospital Sir David Sloman, Chief Executive Royal Free Hospital 4

DELIVERING THE PROMISE OF CELL, GENE AND REGENERATIVE THERAPIES

UCL is a world-leader in the clinical clinical trials2 (Figure 2). Through our UCL and partner NHS Trusts clinically translation of cell, gene and regenerative coordinated multidisciplinary network of deliver both in-house and commercial therapies. UCL and partner NHS Trusts researchers, engineers, clinicians, patients, technologies: 38% of trials analysed were participate in 59% of the UK’s advanced health economists and professionals, the UCL-sponsored investigator technology, 9% therapy clinical trials, competing with UCL Cell, Gene and Regenerative Medicine external academic sponsored technology, US institutions such as Harvard and the Therapeutic Innovation Network (CGRM 18% licensed UCL technology and 35% University of Pennsylvania and with top TIN) has established a strong pipeline that commercial partner technology. European countries in terms of clinical is delivering to patients and to the UK’s activity2 (Figure 1). In the UK, UCL is the industrial ambitions. lead participant in advanced therapies

Figures 1 & 2. Participation in advanced therapy clinical trials September 2017. Institutions participating in two or more trials are shown. Data source: clinicaltrials.gov.

60 35 UCL Institution sponsored External institution sponsored 30 50 Licensed technology Other commercial sponsor

25 40

15 Number of trials Number of trials

20 10

10 5

0 0 UK KCL UCL Italy Spain Bart’s Wirral Leeds Bristol UPenn Oxford Cardiff France Guilford Harvard Imperial Glasgow Sheffield Germany Plymouth Aberdeen Cambridge St George’s Nottingham Manchester Netherlands Birmingham Southampton Edinbuorough 5

First-in-human gene-edited T-cells: Layla Richards received gene-edited CAR-19 We are delivering multiple T-cells for relapsed acute lymphoblastic leukaemia at GOSH in 2015. The treatment was technologies, many first-in-human pioneered by GOSH BRC researchers led by Professors Waseem Qasim in collaboration (FIH), across multiple disease areas in with biotech company Cellectis. Credit: Great Ormond Street Hospital. clinical trial and as specials.

UCL and partner NHS Trust clinical firsts FIH gene therapy for Haemophilia B FIH optimised Factor VIII gene therapy for Haemophilia A FIH Haematopoietic stem cell gene therapy for Primary Immune Deficiencies FIH gene-edited T-cells FIH WT1-TCR engineered T-cells First UK CAR-T translational programme FIH embryonic stem cell-derived cells for macular degeneration Proof-of-concept gene therapy for retinal dystrophy FIH tissue engineered tracheal implant FIH novel TIPS biomaterial for tissue regeneration FIH maternal gene therapy for foetal growth restriction (in set-up) UK’s first accredited GMP stem cell lab

34 >50 clinical trials clinical products released active in 2017 to patients in 2016 GMP facilities 6

OUR COLLECTIVE CAPABILITIES

UCL recognises that multiple stakeholders are needed to successfully deliver cell, gene and regenerative therapies with complex manufacturing and regulatory requirements. We offer end-to-end translation of advanced therapies through multi-disciplinary working, productive partnership with industry and access to extensive translational infrastructure encompassing three NIHR Biomedical Research Centres (BRCs). Our capabilities enable us to mature an idea from UCL’s extensive science base, validate with pre-clinical and clinical proof-of-concept (POC) studies and to commercialise opportunities (Figure 3).

Figure 3: End-to-end translation of advanced therapies

T T Clinical Delivery Assets to address • Expertise in • Monitoring • Licensing high unmet need trial design • Import/Export • Strategic Collaborations Seed funding • Protocol writing • QP release • New company creation • ATMP dossier • Logistics • Venture capital funding

Technology Portfolio Scientific & business strategy Commercialisation • >£1M internal seed fund Preclinical Proof of Concept • Professional business managers • Multiple disease areas Clinical Proof of Concept • Intellectual property filing strategy • Key expertise in addressing • Market analysis manufacturing challenges • Licensing deals • New company creation T • Access to venture capital funding 7

OUR COLLECTIVE CAPABILITIES: TRANSLATIONAL EXPERTISE

UCL’s translational infrastructure is co- are critical in delivering our ambitions in trial design (Institute of Clinical Trials and ordinated both within the university and at the field. The Cell, Gene and Regenerative Methodology), sponsorship (JROs) and partner NHS Trust hospitals. UCL’s three Medicine Therapeutic Innovation Network operations (Clinical Trials Units – CTUs, NIHR BRCs University College London (CGRM TIN) brings together over 100 Clinical Research Facilities – CRFs), Hospital (UCLH), Great Ormond Street researchers across the university and partner commercialisation (UCL Business), partner Hospital for Children (GOSH) and Moorfields hospitals to share expertise and maximise hospitals (NIHR BRCs) and NHS adoption Eye Hospital (MEH) received over £167 strategic opportunities. Key resources in (UCL Partners) align in order to accelerate million of renewed funding in 2016, the pre-clinical development (Translational delivery of advanced therapies to our largest share of any UK university. BRCs and Research Office – TRO), industrialisation patients (Figure 4). Partner NHS Trusts have made significant of manufacture (Faculty of Engineering, investments in the development of our GMP facilities), regulatory expertise (TRO, cell, gene and regenerative therapies and Joint Research Offices – JROs), clinical

Figure 4: Extensive infrastructure accelerates the translation of advanced therapies

CG IN R T M M T R IN G GMP C facilities NIHR Translational Biomedical Largest Research Research aggregation Office Centres of biomedical adoption science Institute of UCL Clinical Health in europe Business and

Joint Methodology

Research C

N Office, R I

T CTUs, CRFs

I R N

G C 8

OUR COLLECTIVE CAPABILITIES: ADVANCED THERAPIES PORTFOLIO

Our advanced therapies pipeline has and embryonic stem (ES) cell therapy for therapy products for rare neurological and breadth and depth across technologies retinal disease, tissue engineered products metabolic disease and tissue engineered and disease areas (Figure 5). High-profile for respiratory disease and antisense products including liver, musculoskeletal technologies include gene-modified therapy for Huntington’s disease (HD) and and neural tissue, as well as exciting new haematopoietic stem cells (HSCs) for Duchenne Muscular Dystrophy (DMD). technologies such as foetal gene and stem primary immune deficiencies (PID), CAR-T Next generation constructs and application cell therapies. Supportive technologies (chimeric antibody receptor) and TCR to new disease indications are in include extensive biomaterials science, (T-cell receptor) for haematology and development for many of these therapies. novel delivery and imaging techniques, oncology, gene-editing for haematology, The pipeline also includes a substantial innovative human tissue models and big adeno-associated virus (AAV) gene therapy translational portfolio of AAV gene data capabilities.

Figure 5: Key therapies in UCL’s cell, gene and AAV gene therapy Gene modified • Rare disease • Metabolic disorders Maternal CAR-T, TCR Gene editing regenerative pipeline • Neurological disease • Neuromuscular disease gene therapy skin cells • Cancer • Leukaemia • Inherited skin disease Our advanced therapies pipeline is supported by Non-viral Foetal stem cell CAR-T γδ Next generation AAV gene therapy Gene Gene extensive funding from T-cell therapy Next generation gene therapy and gene therapy CAR-T, TCR gene modified HSCs • Haemophilia modified MSCs modified HSCs Research Councils, NIHR, Leukaemia • Retinal disease • Lung cancer • PID charities, government and industry, including but not limited to those listed on DISCOVERY PRE-CLINICAL CLINICAL DELIVERY & DESIGN DEVELOPMENT page 9. In a review of UCL’s (OR SET-UP) advanced therapies activity, over £165 million active Novel delivery Next generation Cell therapy Muller stem Next generation Corneal stem cells funding was identified in a cell therapy MSCs Adoptive T-cells • Corneal & conjunctival mechanisms tissue engineering • Nerve repair adoptive T-cells • Tendinopathy • Post-HSCT 14 month period (2014/15)3. • Retinal disease disease Internal seed funding supported by the MRC, Tissue engineering Novel IPSC, TIPS novel Tissue engineering Wellcome Trust and our three • GastrointestinaI • Musculoskeletal • Neural devices ES-derived cells biomaterial • Respiratory organs Stem cell therapy • Liver • Respiratory tissue • Macular & retinal disease • Fistula NIHR BRCs accelerates • Cardiovascular, GI, the transition of discovery musculoskeletal, renal disease, Antisense science to early stage tissue repair Automated gene-modified therapeutic development. Novel biomaterials technology HSC & T-cell therapies • DMD • HD 9

Our funders include

AAV gene therapy Gene modified • Rare disease • Metabolic disorders Maternal CAR-T, TCR Gene editing • Neurological disease • Neuromuscular disease gene therapy skin cells • Cancer • Leukaemia • Inherited skin disease

CAR-T γδ Non-viral Foetal stem cell Next generation Next generation AAV gene therapy Gene Gene gene therapy and gene therapy T-cell therapy CAR-T, TCR • Haemophilia modified MSCs modified HSCs Leukaemia gene modified HSCs • Retinal disease • Lung cancer • PID

DISCOVERY PRE-CLINICAL CLINICAL DELIVERY & DESIGN DEVELOPMENT (OR SET-UP)

Muller stem Novel delivery Next generation Cell therapy Next generation MSCs Adoptive T-cells Corneal stem cells mechanisms tissue engineering • Nerve repair cell therapy • Corneal & conjunctival • Retinal disease adoptive T-cells • Tendinopathy • Post-HSCT disease

Tissue engineering Novel IPSC, TIPS novel Tissue engineering • GastrointestinaI • Musculoskeletal • Neural devices ES-derived cells biomaterial • Respiratory organs Stem cell therapy • Liver • Respiratory tissue • Macular & retinal disease • Fistula • Cardiovascular, GI, musculoskeletal, renal disease, Antisense tissue repair Novel biomaterials Automated gene-modified technology HSC & T-cell therapies • DMD • HD >£165M >130 grants projects in 2014/15 discovery pipeline 10

OUR COLLECTIVE CAPABILITIES: MANUFACTURING

UCL’s innovative Department of to personalised medicine manufacturing. in the production of gene therapy, cell Biochemical Engineering provides key The Hub will address the manufacturing, therapy, gene-modified cell therapy and expertise in addressing the complex business and regulatory challenges to ensure tissue engineered ATMP production, as manufacturing challenges associated that new targeted biological medicines well as QP (Qualified Person) expertise. with the production of cell, gene and including advanced therapies can be Centre for Cell, Gene and Tissue regenerative therapies. With expertise developed quickly and manufactured cost Therapeutics (CCGTT), Royal Free Hospital in translation of manufacture to industrial effectively to accelerate widespread clinical Cellular Therapies manufacturing unit, scale, regulatory science and cost and adoption. The world-class training offered GOSH – pending expansion into Zayed reimbursement models, the department by Biochemical Engineering in advanced building (2018) helps to bridge the gap between discovery therapies manufacturing is described on science and routine patient care. In page 14. Cells for Sight Stem Cell Therapy Research 2016 UCL Engineering was awarded Unit, MEH Advanced therapy medicinal product the prestigious EPSRC Future Targeted UCL Wolfson Gene Therapy Unit (ATMP) manufacture for clinical delivery Healthcare Manufacturing Hub, engaging is facilitated by four Good Manufacturing academics across the UK as Spokes to Practice (GMP) facilities with capabilities drive a paradigm shift from one-size-fits-all

Figure 6. Projected demand for pan- 35,000 London academic AAV GMP manufacture. Whilst industry requirements for ATMP manufacture 30,000 have clearly been articulated1, UCL’s CGRM TIN in collaboration with King’s College London, Imperial 25,000 College London and MedCity have quantified

vg 20,000 future GMP manufacturing requirements stemming 6 from the academic base pan-London4. The report presented to the London Academic Health 15,000 AAV/10 Science Centres/ Networks Executive Group in 2017 identified significant increases in demand 10,000 for GMP manufacture of viral vectors (AAV shown here), cellular and tissue-engineered products by 5,000 2021 and is being used to support a London-wide 0 dialogue around innovative capacity solutions. 2016- 2017- 2018- 2019- 2020- 2017 2018 2019 2020 2021

clinical products GMP facilities released to >50patients in 2016 11

OUR COLLECTIVE CAPABILITIES: COMMERCIALISATION

UCL Business (UCLB) realises the commercial potential of research Spinout Companies activity through patents, licensing deals, funding opportunities (UCL Technology Fund, Apollo Fund – a university-industry consortium) and the creation of spinout companies. In the field of academic cell, gene and regenerative therapies, UCLB have helped to forge the pathway to commercialisation by the creation of spinout companies including Puridify (now part of GE Healthcare) in 2014, Freeline Therapeutics, Athena Vision (now part of Meira GTx) and Autolus in 2015 and Orchard Therapeutics, Achilles Therapeutics and Engitix in 2016. Over £295 million in investment has been raised by these companies through sequential financing rounds. Projects continue to be licensed from the academic pipeline into these companies, as well as products licensed to other companies such as Cell Medica and Biomarin.

Our spinouts continue to work with us, giving them access to the originators of the technology, insight into the cutting- edge technology leading to improvements of the products, as well as expert disease understanding and access to the clinical infrastructure and patient cohorts required for delivery. These industry relationships are set to continue and widen to other partners as our reputation continues to grow, allowing us to learn from one another and deliver these novel treatments to our patients.

patents spinout filed companies >£295M investment in spinouts by 2018 12

OUR COLLECTIVE CAPABILITIES: PARTNERSHIPS

Realising the promise of cell, gene and regenerative therapies cannot Partnerships are pivotal to our success be done in isolation. Successful partnerships with the NHS, academia and we are continually seeking to create new, multidisciplinary alliances with and industry underpin UCL’s translational processes. patient-centric organisations from a This brochure highlights how UCL working Our collaborative approach has been variety of sectors. There are multiple in partnership with its three BRCs and recognised with the recent awards of: reasons why you may wish to enagage partner NHS Trust hospitals has aligned with ATMP research and development A £10 million EPSRC grant for the Future to significantly drive forward the field within our organisation: Targeted Healthcare Manufacturing of advanced therapies. This has been Hub – driving the shift from one-size- To access world-class cutting edge science achieved in collaboration with Higher fits-all manufacturing to personalised (novel targets, novel vector design, gene Education Institutions across the UK, manufacturing. editing approaches, novel manufacturing Europe and worldwide. In addition, we solutions, novel imaging of cell and gene have forged links with Industry and A prestigious 15 million Euro Horizon 2020 therapies etc) Contract Research Organisations (over teaming grant (one of only 10 awarded) 70 partnerships) to deliver in the areas of to establish the EU Discoveries Centre for To access clinicians and patients to better translational research, GMP manufacturing Regenerative and Precision Medicine in understand/position your therapies for use and testing, regulatory consultancy etc, Portugal, sharing our translational expertise To access expertise in clinical operations making use of the very best expertise, in accelerating delivery of advanced to deliver advanced therapy trials (UCL and advice and resource wherever it resides. therapies across Europe. its partner hospitals currently participate Industry and others are able to draw on Working across London Higher Education in 59% of active advanced therapy trials in the expertise of our advanced therapies Institutes and NHS trusts via the Academic the UK)2 community through the services of UCL Health Science Centres to join up advanced Consultants. Key opinion leaders in the therapy activity pan-London5, especially Partnership between Professors field have advised industry ranging from addressing the area of vector and cell Emma Morris and Hans Stauss and SME to large pharmaceutical companies. In manufacture capacity for the future4. cellular therapeutics company Cell addition, our close dialogue with regulators Medica is accelerating UCL’s novel from an early stage in development helps to TCR technology by generating shape and inform the regulatory pathway. leading-edge modified TCR products for the treatment of cancer.

> > commercial70 partners consultancies25 13

OUR COLLECTIVE CAPABILITIES: PUBLIC & PATIENT INVOLVEMENT

UCL and partner NHS Trusts hospitals/BRCs are keen for patients and the public to be actively involved in our research, not just as participants but in helping to design and conduct our work. Patient and public involvement (PPI) in research can lead to treatments that better meet the needs of users and the public, and to research results that are more likely to be put into practice.

UCLH/UCLH BRC provides training, advice GOSH/GOSH BRC engages patients and MEH/MEH BRC invites patients and staff to and support for researchers to enable them the public in research by actively consulting, focus groups and patient panels, allowing the to better involve patients and the public in involving and listening to their views on hospital to understand some of the issues research. Groups of lay people meet on a GOSH research, as well as aiming to raise facing the trust and to enabling patients and regular basis and, together with patients, awareness of research carried out by BRC staff to work together to find solutions. they can provide input into the strategic and GOSH researchers. The Young Person’s direction of research as well as advising on Advisory Group consists of children and elements of a particular research study such young people aged between 8–21 that as looking at grant or ethics applications, meet at GOSH and provide feedback to reviewing plain English summaries or researchers to help them carry out research advising on how best to recruit patients to that is relevant to children and young people. trials. UCL and UCLH are also working hard The Parent/Carer Research Advisory Group to deal with the more challenging areas of consists of parents or carers who have a child PPI, including the input of patients and the with a health condition and provides advice public in early stage lab-based research. on improving research into child health. 14

OUR COLLECTIVE CAPABILITIES: TRAINING THE NEXT GENERATION – ADDRESSING THE SKILLS GAP

The potential for cell, gene and regenerative around challenges in advanced therapies Regulatory Science for Advanced Therapies therapies to radically transform the life of manufacturing. – Bench to Medicine: Four day course in patients is fast becoming a reality. Significant partnership with the British Society of Gene Education challenges remain however, not least: and Cell Therapy and the Cell and Gene MSc/PGDip/PGCert programme in Cell and Therapy Catapult Educating patients and clinicians on the Gene Therapy potential of advanced therapies Academic Careers Office skills training: BEng/MEng Regenerative Medicine MiniMD: Two-week clinical immersion Working with industry to upskill the existing Manufacturing Minor programme for non-clinical biomedical workforce, as well as training the new scientists; Ignite: medical innovation workforce needed to manufacture these Training summit for group leaders to engage with therapies MBI® module: Cell and Gene Therapy innovation from a variety of perspectives Training more qualified persons (QPs) Bioprocessing. This course is a component UCL Innovation and Enterprise: of UCL Biochemical Engineering’s award- Increasing the number of regulatory advisors Entrepreneurship and business interaction winning programme of Modular Training for are supported by training, funding and Enhancing the clinical infrastructure at the Bioprocess Industries. business services for staff, students and hospitals to deliver these novel therapies Human Pluripotent Stem Cells in Culture: external entrepreneurs UCL is currently addressing the recognised Hands-on, basic cell culture training course UCL partnership with the Centre for the skills gaps1 by running accredited courses focusing on induced pluripotent stem cells Advancement of Sustainable Medical aimed both at students and at industry and human embryonic stem cells. Innovation (CASMI): Building innovative looking to up-skill their employees. We are Biochemical Engineering and Bioprocess solutions to barriers in the translation of the working to expand our offering over the next Leadership EngD. advanced therapies five years. UCL’s Department of Biochemical Engineering are pivotal in addressing training

UCL ADVANCED CENTRE FOR UCL ADVANCED CENTRE FOR BIOCHEMICAL ENGINEERING BIOCHEMICAL ENGINEERING

Advancing Stem Cell Cell & Gene Training Therapy Course: Bioprocessing Human & Manufacture Pluripotent Stem Cells Focusing on taking discoveries from lab to clinic and acquiring in Culture new skills sets to achieve this

2016 – 2017* 09 – 11 JULY 2018

Held at the Department of Biochemical Held at the Department of Biochemical Engineering, UCL, UK Engineering, UCL, London, UK

*Course date is flexible, will run once cohort is confirmed – maximum 4 participants.

A 3-day hands-on course designed to equip life science and engineering Short Courses & Training graduates with the practical skills ENTERPRISE AWARD FOR in Biochemical Engineering CPD AND SHORT COURSES necessary to maintain pluripotent 2014 stem cell lines

1083_13_MBI_Cell & Gene Therapy Bioprocessng_A5_4pp copy.indd 1 30/07/2017 21:31 15

Professor Professor Bobby Gaspar Adrian Thrasher CLINICAL CASE STUDY Gene-Modified Cell Therapy for Rare Disease

A team led by clinician scientists Professors Bobby Gaspar and Professors Gaspar, Thrasher and Professor Adrian Thrasher at UCL’s Great Ormond Street Institute of Child Waseem Qasim (also GOS ICH) founded spinout company Orchard Therapeutics Health and partner hospital GOSH have pioneered the use of gene in 2016 to advance and commercialise therapy for rare diseases in children. the group’s ex vivo gene therapy platform. Orchard was created by UCL’s technology With a focus on primary immune are in the clinical pipeline. In addition, transfer company UCL Business PLC deficiencies (PIDs), the team has extending the technology to gene-modify and F-Prime Capital Partners, securing developed the technique of ex vivo other cell types such as T-cells and £21 million in Series A financing. The gene therapy of autologous (patient) fibroblasts has widened the scope to company has partnerships with UCL, haematopoietic stem cells in order to treat diseases including haematological GOSH, University of Manchester, University correct a disease’s underlying genetic disorders and skin disease. of California Los Angeles, and Boston defect. The combination of GOS ICH’s Children’s Hospital. world-class academic environment, “We’ve made considerable progress in GOSH’s unique patient population this field over the past decade. Gene and GOSH BRC support has enabled therapy has been refined, trialled the team to progress the innovative in patients and we’ve learnt a huge technology through in vitro and in vivo amount. Studies we have designed here proof-of-concept (POC) studies and are now open in Los Angeles, Boston, into clinical trial. The team have now led Paris and other international centres. seven early phase clinical trials for PID Professor Adrian Thrasher including adenosine deaminase severe combined immune deficiency (ADA-SCID), “With support, we believe that a decade X-linked SCID, Wiskott-Aldrich Syndrome further on, gene therapy will be able and X-linked Chronic Granulomatous to improve the life and health of many Disease, restoring immune function children with life-threatening diseases, to patients with minimal side effects where other treatment methods are either in the majority of cases. Therapies for ineffective or non-existent. It’s a very PIDs including Fanconi Anaemia and exciting time to be working in this field.” p47phox-deficient CGD (with support Professor Bobby Gaspar from the UCL Technology Fund) and Mucopolysaccharidosis IIIA Sanfilippo 16

Professor Professor Dr Martin Pule Emma Morris Hans Strauss CLINICAL CASE STUDY T-Cell Engineering

T-cell engineering is changing the face of clinical haematology and has the potential to do likewise in areas such as oncology and autoimmune disease. UCL investigators strongly supported by the UCLH BRC are at the forefront of both CAR-T and TCR T-cell engineering technologies.

CAR-T “It is exciting to be involved in Autolus, The team have developed a TCR that recognises the WT1 antigen, a protein over- Dr Martin Pule, a clinician scientist at where we have an opportunity to bring expressed in a number of haematological the UCL’s Cancer Institute, has driven the innovative new therapeutic approaches malignancies and solid tumours. Following evolution of CAR-T technology in the UK. to patients who often have no alternative the demonstration of proof-of-concept CAR-T cells are genetically modified with treatment path. The key will be to (POC) in vivo, the team obtained MRC a chimeric antigen receptor that re-directs remain at the cutting-edge of T-cell funding to test the safety of WT-1 TCR in the specificity of the patient’s T-cells, engineering to create a new generation AML and CML in a phase I/II clinical trial allowing clonal killing of cells expressing the of programmed T-cells acting as sponsored by the Cell Therapy Catapult. chosen surface antigen. Dr Pule has built a autonomous agents to kill tumour cells. Results indicate excellent persistence of substantial translational CAR-T programme, What we’ve seen so far in the CAR T-cell gene-modified T cells and ongoing cohorts establishing the largest portfolio of CAR-T field is only the beginning.” are exploring the relationship between T clinical trials in Europe with eleven early Dr Martin Pule cell dose and efficacy. Catapult Therapy phase trials open at UCL partner hospitals TCR Ltd, a joint venture company set-up UCLH and GOSH in 2018. TCR by the Cell and Gene Therapy Catapult, Dr Pule is founder of the UCL spinout An alternative T-cell engineering strategy UCLB and Imperial Innovations to advance company Autolus, launched in 2015 is being pioneered by Professors Emma the WT-1 TCR technology, was acquired by to develop and commercialise a new Morris and Hans Stauss of UCL’s Institute cellular therapeutics company Cell Medica generation of CAR-T cell therapies. Autolus of Immunity and Transplantation. Expression in June 2017. Collaboration with Cell Medica was created by UCL Business PLC and of a recombinant T-cell receptor (TCR) re- is driving the development of second healthcare investment company Syncona directs the specificity of a patient’s T-cells, generation TCR constructs. LLP, securing an initial £30 million in facilitating recognition of the TCR’s cognate investment, followed by a further £40 million epitope presented in the context of major from Woodford Investment Management histocompatibility antigens (MHC) on the cell and Perceptive Bioscience Investments in surface. TCR strategies are MHC-restricted but 2016. Dr Pule was named BBSRC’s Most have the advantage of recognizing intracellular Promising Innovator in 2016. antigens processed and expressed at the cell surface, a feature that may be advantageous for targeting solid tumours. 17

Professor Professor Amit Nathwani Robin Ali CLINICAL CASE STUDY AAV Gene Therapy

UCL has a significant pipeline of adeno-associated virus (AAV) gene therapies including treatments for Haemophilia and inherited retinal disorders in clinical trial and treatments for rare neurological and metabolic disease in translation.

Haemophilia Institute of Health Research, UK Medical Research Council and industry. As chief In 2016, Professor Amit Nathwani of the Professor Nathwani is founder, member investigator, Prof Ali established one of the UCL Cancer Institute and Director of the and Chief Scientific Officer of Freeline world’s first clinical trials of gene therapy Katharine Dormandy Haemophilia Centre Therapeutics, a spinout company launched for retinopathy (Leber Congenital Amaurosis at the Royal Free Hospital, was awarded in 2015 by UCL Business PLC and Syncona Type 2). The trial reported an improvement the European Society for Gene and Cell LLP with an initial investment of £33 million. in vision and contributed to POC of gene Therapy’s Outstanding Achievement Award Freeline Therapeutics builds on Professor therapy as a treatment for inherited retinal for his pioneering work on gene therapy for Nathwani’s AAV gene therapy platform degeneration. Prof Ali has worked closely Haemophilia. In 2010, in collaboration with technology to drive the clinical translation with the TRO to drive the pre-clinical St. Jude Children’s Research Hospital, a and commercialisation of treatments for development and clinical trial of optimised team led by Professor Nathwani was the first bleeding disorders and other disorders that AAV vectors for LCA and achromatopsia in the world to show correction of bleeding affect the liver. type 3, with GMP manufacture of viral in patients with severe Haemophilia B by Inherited retinal disorders vectors at the UCL Wolfson Gene Therapy using AAV-based gene transfer to express facility. These early phase clinical trials, now Factor IX. Since demonstrating clinical POC, Professor Robin Ali of the UCL Institute active, are supported through public and Prof Nathwani has extended this technology for Ophthalmology (IoO) and theme leader private funding, including from MeiraGTx, a to other inherited bleeding disorders, for gene Therapy at MEH NIHR Biomedical company of which he is a Founder and Chief working with the UCL TRO to develop Research Centre, has pioneered the Scientific Officer. translational pathways for Haemophilia A development of AAV-based gene therapy for and for Factor VII deficiency. Partnership eye disease. His functional rescue of retinitis with biotechnology company Biomarin in pigmentosa in vivo in 2000 established the form of a licensing deal has enabled POC for ocular gene therapy and his team the progression of Haemophilia A gene have since demonstrated in vivo POC for therapy into phase I/II clinical trial in the gene therapy of a wide range of ocular UK; Biomarin has built its first gene therapy disorders, including retinal dystrophies, manufacturing facility to support GMP ocular angiogenesis and uveitis. In doing so, manufacture of the Factor VIII therapy for he has established a pipeline of therapies, clinical trial and commercial production. supported by charities, UK National 18

Professor Professor Julie Daniels Mark Lowdell CLINICAL CASE STUDY Cell Therapies

Cell therapies developed at UCL and partner NHS Trust hospitals are being used to treat a range of diseases including eye diseases, tendinopathy and leukaemia. The expertise of the Cells for Sight (Director: Professor Julie Daniels) and CCGTT (Director: Professor Mark Lowdell) GMP facilities has been fundamental to the pre-clinical development and GMP manufacture of these therapies.

Stem cells Professors Astrid Limb and Sir Peng Adoptive T-cells Khaw are developing use of the Muller Professor Julie Daniels of the IoO has UCL investigators have been pivotal in the Stem cell, discovered at the IoO and established a translational programme of evolution of adoptive T-cell therapies in the field named the Moorfields IO cell, for treatment research encompassing the use of stem of haematopoietic stem cell transplantation of retinal degeneration. This therapy is cells and tissue engineering for diseases of (HSCT). Professor Steven Mackinnon and being translated with support from Apollo the cornea and conjunctiva. Prof Daniels Professor Karl Peggs of the Cancer Institute Therapeutics. is founding director of the MEH Cells for developed the use of virus-specific donor Sight Stem Cell Therapy Research Unit, Mr Andrew Goldberg of the Institute of T-cells for the reconstitution of recipient the UK’s first accredited cultured stem cell Orthopaedics and Musculoskeletal Science anti-viral responses post-allogeneic HSCT facility. The Cells for Sight GMP facility and orthopaedic surgeon at the Royal National and demonstrated efficacy in the context of manufactures cultured corneal stem cells Orthopaedic Hospital, leads a phase II trial of cytomegalovirus (CMV) in early clinical trials. on a compassionate basis for patients with autologous mesenchymal stem cells for repair Phase II clinical trials to assess pre-emptive blinding ocular surface disease. of Achilles Tendinopathy. The cells are cultured efficacy in the matched sibling and unrelated from patient bone marrow at the CCGTT GMP donor settings have been sponsored in Professor Pete Coffey of the IoO is director facility. A second pilot study assessing the partnership with cellular therapeutics company of the London Project to Cure Blindness, role of stem cells in ankle arthritis is in process Cell Medica. The use of allodepleted donor T-cell an MEH-NIHR collaboration aiming to bring which is also developing novel ways to assess populations to safely reconstitute the immune pioneering stem cell therapy for retinal a patient’s regenerative capacity. system post-HSCT has been developed by diseases to the clinic. In 2015 in a phase I Professor Persis Amrolia of ICH GOS and clinical trial sponsored by Pfizer, patients with Professor Sam Janes of the Division of Professor Ronjon Chakraverty of the Cancer Acute Wet Age-Related Macular Degeneration Medicine has developed a therapy for Institute. Prof Amrolia’s technology, translated to were treated with human embryonic stem lung cancer using genetically-modified phase I/II clinical trial with the support of the TRO cell-derived retinal pigment epithelium cells mesenchymal stem cells expressing the TNF- and the Cancer Research UK and UCL Cancer manufactured at the Cells for Sight GMP facility. related apoptosis inducing ligand TRAIL. An Trials Centre, depletes alloreactive T-cells based Prof Coffey’s translational programme is now MRC-funded phase I/II clinical trial has MHRA on expression of cell surface markers CD25 and investigating alternative stem cell sources approval and is in set-up, with GMP cells CD71; Prof Chakraverty’s technology, currently including induced pluripotent stem cells. being manufactured at the CCGTT facility. in phase II clinical trial, removes CD8 T-cells from the donor T-cell infusion. 19

Professor Professor Martin Birchall Paolo de Coppi Richard Day CLINICAL CASE STUDY Tissue Engineering and Biomaterials

UCL’s groundbreaking Tissue Engineering The UCL Centre of Nerve Engineering The first clinical trial of a UCL-developed group comprises cell and developmental is another example of interdisciplinary biomaterial for tissue regeneration is the FIH biologists, biomaterials scientists, working to achieve translational success. phase I/II clinical trial of thermally-induced biochemical engineers, clinician scientists Launched in 2017 by cellular biologist phase separation (TIPS) microparticles for and GMP manufacturers. Professors Martin Dr James Phillips from the School of the treatment of perianal fistulas. Developed Birchall of the Ear Institute, Paolo de Pharmacy and Mechanical Engineering’s by Division of Medicine’s Dr Richard Day, Coppi of ICH GOS and Mark Lowdell of the Dr Rebecca Shipley, the Centre’s vision is TIPS provide a scaffold structure that cells Cancer Institute developed, manufactured “to create a multidisciplinary, inter-faculty can easily grow between and into. The and performed FIH tissue-engineered adult research centre that translates diverse and clinical translation of TIPS technology, and paediatric tracheal tissue implants complementary research in the physical designated a class III medical device, has constructed from decellularized donor and life sciences at UCL to clinical nerve been supported by the UCLH BRC, UCL trachea seeded with recipient mesenchymal repair”. Dr Phillip’s work developing tissue TRO and JRO. The knowledge gained in stromal cells. Phase I/II clinical trials for engineered neural tissue for nerve repair is device regulations and manufacture will tissue engineered laryngeal, tracheal and supported by the UCL Technology Fund. serve as a foundation for the translation of oesophageal implants are active/in set-up. our significant biomaterials pipeline. Professor Massimo Pinzani and team from the Division of Medicine have pioneered the development of tissue-engineered liver, and other tissue-engineered products in development at UCL include diaphragm, lung, liver, pancreas, small intestine, stomach, bladder, musculoskeletal and craniofacial tissue. HOW TO ENGAGE WITH US

In 2014 we established a team within the UCL If you would like to work with us to Translational Research Office dedicated to deliver on the promise of cell, gene and the development and alliance management of regenerative therapies, please contact strategic partnerships, working closely with Dr Chloe Marden (CGRM TIN Strategic our technology transfer office UCL Business Coordinator) at [email protected] and with Research Services to deliver a We very much look forward seamless package for engagement. Dr Chloe to working with you. Marden

CELL, GENE AND REGENERATIVE THERAPIES AT UCL AND PARTNER TRUSTS World leaders in the translation of advanced therapies

REFERENCES LINKS

1. Advanced Therapies Manufacturing www.ucl.ac.uk/translational-research Taskforce Report 2016 www.ucl.ac.uk/jro www.uclhospitals.brc.nihr.ac.uk 2. Clinical trials.gov analysis of cell, gene www.gosh.nhs.uk/research-and-innovation/nihr-great-ormond-street-hospital-brc and regenerative medicine clinical trials www.moorfields.nhs.uk/content/nihr-moorfields-biomedical-research-centre www.ucl.ac.uk/ictm open in September 2017 https://uclpartners.com 3. Advanced Therapies Scoping Review www.ucl.ac.uk/biochemeng/research/hub www.ucl.ac.uk/cells-for-sight/cell-therapy 2015, UCL Translational Research Office www.ucl.ac.uk/cancer/research/department-clinical-trials/wolfson-gene-therapy-unit 4. Pan-London academic GMP www.uclb.com www.ucl.ac.uk/consultants requirements for cell, gene & www.uclh.nhs.uk/PandV/Getinvolved/Pages/Home.aspx regenerative therapies 2016-2021: UCL, www.gosh.nhs.uk/research-and-innovation/nihr-gosh-brc/patient-and-public-involvement King’s College London, Imperial College www.moorfields.nhs.uk/content/patient-experience London, MedCity, 2017. www.ucl.ac.uk/biochemeng/research/mbi/courses/CellandGeneTherapy www.ucl.ac.uk/biochemeng/research/mbi/courses/hpscc 5. £5M HEFCE Connecting Capabilities www.ucl.ac.uk/prospective-students/graduate/research/degrees/biochemical-engineering-bioprocess- Fund award: King’s College London, leadership-engd UCL, Imperial, MedCity www.ucl.ac.uk/lifelearning/courses/regulatory-science-advanced-gene-cell-therapy http://casmi.org.uk www.nerve-engineering.ucl.ac.uk