ESGCT and NVGCT Collaborative Congress: the Hague - 23 to 26 October Abstracts HUMAN GENE THERAPY XX:A2–A121 (XXXX 2014) ª Mary Ann Liebert, Inc
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ESGCT and NVGCT Collaborative Congress: The Hague - 23 to 26 October Abstracts HUMAN GENE THERAPY XX:A2–A121 (XXXX 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/hum.2014.2536.abstracts Invited Speakers INV001 & INV002 Viruses have two faces. On the one hand they can cause harm Lessons learned for therapy development for Duchenne and illness, and the virus may manifest directly as a contagious muscular dystrophy disease. A viral infection can also have delayed consequences, and Elizabeth Vroom45Annemieke Aartsma-Rus123 in rare cases, may cause cellular transformation and cancer. On the other hand viruses may provide hope for an efficacious 1: Leiden University Medical Center 2: Newcastle University treatment of serious disease. Examples of the latter are the use of 3: TREAT-NMD Alliance 4: Duchenne Parent Project viral vaccines, viral gene-transfer vectors in experimental gene- Netherlands 5: United Parent Project Muscular Dystrophy therapy, or as therapeutic anticancer agent in an oncolytic-virus therapy setting. Already there is evidence for antitumor activity of Duchenne muscular dystrophy is a severe muscle wasting dis- oncolytic viruses, although in many studies therapeutic efficacy is order that affects *1in5000new-bornboys.Patientsgenerally relatively rarely seen. This demands for more efficacious viruses. loose ambulation at around 12 years of age, need assisted ventilation There are several options for improving the anticancer efficacy. before their twenties and die in the 2–4th decade. The disease is We can use genetic modification (reverse genetics) strategies to caused by mutations in the DMD gene that abolish production of enhance their oncolytic activity, but should do so without com- functional dystrophin. The causative gene was identified in 1986, promising their safety. Likewise we can increase their specificity but the first drug for Duchenne (Translarna, previously Ataluren/ but should take care not to thwart their antitumor efficacy. Alter- PTC124) received conditional marketing approval in Europe only in natively, we can use classical bioselection (forward-genetics) August 2014. This drug only applies to a subset of patients and many strategies to isolate mutants with new phenotypes. Finally we may other therapeutic approaches are in clinical and preclinical devel- exploit the existing viral diversity and evaluate panels of new opment. Several challenges impeded development of drugs for a rare viruses for their antitumor efficacy in human–tumor models, to disease like Duchenne muscular dystrophy. Scientific challenges identify candidates with improved potency. In this presentation I included the size of the gene and protein involved, the abundance of will illustrate the various approaches by some salient examples. skeletal muscle (*30–40% of the body), and the relatively rapid decrease in muscle quality. Clinical challenges included the lack of standardized care and access to good care. Translational challenges involved the lack of expertise with conducting clinical trials and lack INV004 of infrastructure (patient registries, trial site registries, outcome measures, natural history data etc). Regulatory challenges included Evolutional approaches AAV the limited knowledge of regulators on specific rare diseases, such as Hildegard Bu¨ning Duchenne, but also lack of expertise from the Duchenne field in dealing with regulators and requirements for drug approval (func- Center for Molecular Medicine Cologne tional or surrogate outcome measures that measure clinical benefit). Many of these challenges have now been overcome through net- No Abstract available working of researchers, clinicians, Industry and patient representa- tives. In fact patient organisations have been involved in each step of the therapy development process, through funding of basic research and clinical trials, crucial input into development of outcome mea- INV005 sures that correlate with clinical benefit and care standards, partici- pation of patients in trials and meetings with regulators and are Redirecting T cells by chimeric antigen receptors actively involved in identification and development of surrogate Hinrich Abken12 endpoints. In this session a scientist and a patient representative will give their perspective on the lessons learnt and success factors for 1: Center for Molecular Medicine Cologne (CMMC), drug development for Duchenne muscular dystrophy. University of Cologne 2: Clinic I for Internal Medicine, University Hospital Cologne, Cologne Adoptive cell therapy is aiming at targeting defined cells in the INV003 patient by antigen specific T cells. To treat cancer, patient’s T cells are ex vivo engineered with pre-defined specificity for cancer cells, Viruses with Good Intentions: Developing Oncolytic amplified and re-administered to the patient by transfusion. The Agents for Therapy of Cancer targetingspecificityisprovidedbyarecombinantreceptormole- Rob C. Hoeben1 cule, chimeric antigen receptor (CAR), which is composed in the extracellular part of an antibody-derived binding domain for target 1: Section of Virus and Stem Cell Biology, Department recognition, and in the intracellular part of a T cell receptor (TCR) of Molecular Cell Biology, Leiden University Medical Center, derived signaling domain for T cell activation upon target en- PO box 9600, 2300 RC Leiden, The Netherlands gagement. The CAR initiates a downstream signaling cascade A2 INVITED SPEAKERS A3 resulting in pro-inflammatory cytokine release, T cell amplification sult in hemophilia arthropathy and disability and reduced quality of and lytic degranulation leading to the elimination of target cells. life. In order to reduce bleeding symptoms haemophilia patients Due to the particular structure the CAR exhibits several properties are prophylactically treated with intravenously administered co- different to the TCR, including target recognition independently of agulation factor concentrates 2 to 3 times a week, starting in early the major histocompatibility complex, high affinity binding, and childhood. A moderate increase of factor levels results in a dra- recognition of targets which are not physiologically recognized by matic improvement of bleeding phenotype, as patients with mod- T cells like carbohydrates. The TCR CD3 signaling moiety in a erate or mild haemophilia (Factor levels above 1 or 5% of normal, CAR can be combined with costimulatory signaling chains like the respectively) have no spontaneous bleeding. Therefore gene ther- CD28, OX40 or 4-1BB endodomain, giving rise to the so-called apy resulting in expression levels that would allow patients with 2nd generation CAR; combined costimulatory moieties build up a severe hemophilia B to reduce or eliminate their need for pro- 3rd generation CAR. Such CAR T cells can substantially reduce phylactic treatment through endogenous expression of Factor VIII the tumor burden as long as the targeted antigen is present on the or IX may be of enormous benefit. Gene therapy has been suc- cancer cells. Adoptive cell therapy with engineered 2nd generation cessfully used in the academic research setting in a limited number CAR T cells) is achieving impressive efficacy in early phase trials, of patients with severe haemophilia B, primarily using vectors in particular in hematologic malignancies, strongly supporting the based on adeno-associated virus (AAV) serotype 2 and 8. During notion that redirected immune cells can control cancer. We discuss the lecture a summary of recent studies on gene therapy for hae- the pros and cons of the CAR T cell strategy, recent developments mophilia will be presented. Several research groups and companies of TRUCKs, which release a recombinant payload upon CAR are now exploring new developments to improve current treatment engagement into the targeted tumor lesion, and the challenges in strategies to eventually make gene therapy commercially available translating the strategy to clinical practise. for a larger number of patients. Also the background and scientific rationale of a planned gene therapy trial in Europe with AAV-FIX for haemophilia B will be presented. INV006 Genetic info exchange by vesicles Michiel Pegtel INV009 VU University Medical Center Towards a cure for Crigler-Najjar syndrome a collaborate effort of researchers and patients No Abstract available Piter J Bosma1 Ivar de Vette2 1: Tytgat Institute for intestinal and liver disease, AMC, INV007 Meibergdreef 69, 1105BK Amsterdam 2: Najjar Foundation Clinical advances in gene therapy from bench to bedside: a patients’ perspective Crigler-Najjar (CN) syndrome is very rare metabolic liver disorder characterized by the accumulation of unconjugated 1 Adam R Jones bilirubin, the yellow colored degradation product of heme. This 1: University of Sunderland main risk associated with this inherited severe form of jaundice is irreversible brain damage. This can be caused by a high I am 42 and live with severe haemophilia B. Therapeutic concentration of the neurotoxicity of unconjugated bilirubin. In strategies for haemophilia has altered drastically during my life, the absence to lower bilirubin levels severely affected subjects and promises to advance even further in the near future. Though die during their first year of life. As for other rare diseases there are many intriguing scientific and clinical questions that funding to support research to understand the cause of this remain to be answered, one question, above all else, is often disease and to develop a therapy is limited. The Dutch Crigler rationalised and thereby overlooked, or assumed. That question