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Day 1 Day 2
Day 1 - Thursday, February 20, 2014
7:00 Registration & Continental Breakfast
7:55 Welcome & Opening Remarks
Joint Session - Cell & Gene Therapy for Rare Diseases: Research to Regulatory
Moderator: Ian Phillips, Keck Graduate Institute of Applied Life Sciences

Stephen Groft

Director, Office of Rare Diseases Research
National Institutes of Health
  Rare diseases are a growing global concern with resources from many private and public sector organizations required to advance research discoveries leading to discoveries. A global research infrastructure of qualified investigators and multi-national research sites with common protocols and multi-disciplinary research teams are becoming more readily available for rare disease research and orphan products development. Expanding roles have been observed in the patient advocacy groups. The collaboration between academic centers and industry identify potential orphan products for development. There is an expanding interest by the biopharmaceutical industry to provide orphan products for rare diseases. There is an increased understanding and acceptance of the role and value of research networks and consortia for rare diseases research and orphan products development and offer unique clinical research training programs for new investigators. The future remains very bright for the development of orphan products for rare diseases. We now have the ability to attract a critical mass of research investigators with a research interest in rare diseases. There is also a better understanding of how to conduct clinical trials in rare diseases. Research and regulatory agencies have a growing interest in rare diseases and orphan products. The task before us remains daunting as we strive to find better, quicker, and less expensive methods to translate research discoveries to orphan products. Development of products from gene therapy, enzyme replacement therapies, regenerative medicine, refined monoclonal antibodies, small molecules, and repurposing of existing products provide the hope for the millions of people with rare diseases .
8:40 Glybera: First Approved Gene Therapy Product in the EU; What Next?

Harald Petry
Chief Scientific Officer
uniQure B.V.
9:20 Lessons Learned from Two Phase I/II Clinical Trials of Lentiviral Gene Transfer into Autologous CD34+ cells: Planning and Launching International, Multicentre Late Stage Gene Therapy Clinical Trials

Mitchell Finer
Chief Scientific Officer
Severe genetic disease is often treated with allogeneic bone marrow transplantation utilizing a sibling matched donor. Due to the lack of sibling matched donors, matched or partially matched-unrelated donors are used resulting in significant acute and chronic morbidity / mortality for this approach. An alternative is the use of lentiviral vectors encoding a functional gene delivered to autologous C34+ positive cells, followed by autologous transplant. bluebird bio and its collaborators have recently completed a phase I/II study in the treatment of Childhood Cerebral Adrenoleukodystrophy (CCALD) and are currently treating beta-thalassemia major patients in an on-going phase I/II study. Gene-corrected cells were found in the peripheral blood of CCALD and beta-thalassemia major patients > 60 months post-transplantation. Clinical stabilization was documented and maintained for over 60 months – evidenced by MRI assessed lesion stabilization and maintenance of cognitive function in CCALD patients and transfusion independence in beta-thalassemia major patients. Both studies demonstrated safety of the autologous gene transfer approach at 4 – 5 years post treatment. The lessons learned from these studies that enabled bluebird bio and its collaborators to launch multi-center, global clinical trials for the treatment of CCALD and beta thalassemia major will be presented, describing the steps leading up to clinical trial launch in 2013 for both indications which are enrolling in the US and Europe.
9:45 AAV Gene Therapy as a Platform for the Treatment of Rare and Inherited Disease

Karen Kozarsky
Vice President, Research & Development
ReGenX Biosciences
Many rare, inherited diseases are caused by single gene mutations. For those diseases in which the affected gene is known, gene therapy may address the high unmet medical need. Recombinant adeno-associated virus (AAV) vectors derived from novel serotypes of AAV are a platform of choice for many indications, providing high-level and long-term gene expression. This presentation will highlight how these novel AAV serotypes are being used to treat metabolic and neurologic diseases, both in animal models and in the clinic.
10:10 Morning Networking Break
10:45 Translational Studies in Neuromuscular Disease Using Gene Therapeutics

Brian Kaspar
Principal Investigator, The Center for Gene Therapy
Nationwide Children's Hospital
Associate Professor, Department of Pediatrics and Department of Neuroscience
Ohio State University College of Medicine
Gene therapeutics has gained significant attention lately for the ability to effectively deliver gene sequences to target tissues. The central nervous system poses significant challenges for drug delivery due to the complexity of brain and spinal cord structures and the blood brain barrier. We and others have discovered a class of Adeno Associated Virus capable of passing the blood brain barrier or the cerebrospinal fluid to effectively deliver therapeutic payloads to the brain and spinal cord. This talk will focus on recent developments in two neuromuscular diseases including Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis. The presentation will include discussion of pre-clinical efficacy studies as well as safety studies. Additionally, we will discuss the translational studies in spinal muscular atrophy that has resulted in an approved Investigational New Drug Application for Spinal Muscular Atrophy patients.

The talk will highlight:
1) The latest technology in gene delivery for targeting the brain and spinal cord.
2) Therapeutic results in pre-clinical models of devastating neuromuscular disorders including spinal muscular atrophy and amyotrophic lateral sclerosis.
3) Regulatory pathway for an Investigational New Drug Application.
4) The vision for gene based therapeutics.
11:10 Gene Therapy for Hemophilia A

Trent Spencer
Director of Gene Therapy, Pediatrics
Emory University School of Medicine
Hemophilia A and B are monogenic bleeding disorders currently treated by protein replacement therapy. Hemophilia A is more prevalent than B, with an incidence of approximately 1:5,000 male births. Because the deficient/defective protein causing hemophilia B, Factor IX, is less difficult to transfer compared to Factor VIII (FVIII), which is defective in people with hemophilia A, recent gene therapy trials have focused on treating hemophilia B. The development of gene therapy for hemophilia A has been hampered by transgene size, complexity and low-level expression of the FVIII transgene product. We previously bioengineered a FVIII transgene (designated ET-3) that expresses at levels up to 100-fold higher than human FVIII. ET-3 is being used to develop both AAV and lentivirus-based gene therapies for hemophilia A by direct injection or transplant of genetically engineered hematopoietic stem cells, respectively. Vector production does not appear to be a significant hurdle for ET-3 AAV or lentivector-based strategies as high titers of both have been prepared, and several lots of clinically processed recombinant lentivector have been successfully produced. In addition to preclinical efficacy data, various models have shown gene therapy approaches for treating hemophilia is also financially attractive, which further justifies the development of novel curative treatments. Our preclinical data and trial design have been reviewed by the RAC, institutional biosafety programs, and as a pre-IND meeting with the US FDA. This presentation will summarize our gene therapy treatment options for hemophilia A.

“Benefits” of talk:
1) It will be shown that gene therapy is an attractive alternative treatment for hemophilia A.
2) It will be shown that gene therapy offers the potential for long-term elimination of the need for protein replacement therapy, and preclinical and clinical data suggests a long lasting/lifelong treatment is feasible.
3) It will be shown that a bioengineered FVIII, designated ET-3, enables both AAV and lentivector-based treatments for hemophilia A.
4) A gene therapy clinical trial will be described that has been reviewed in a pre-IND meeting with the FDA.

Philip D. Gregory
Chief Scientific Officer
Sangamo Biosciences
12:00 Lunch On Your Own
Emerging Technologies
Moderator: Karen Kozarsky, ReGenX Biosciences
1:30 The Emerging Technology is Intrinsic Biotechnology

Jonathan Sackner-Bernstein
Vice President, Clinical Development and New Technologies
The "boom" in drug development during the 1980s and 1990s leading to the new high tech discipline of "rational drug development”, coupled with the success of the Human Genome Project, led many to believe that our capabilities would rapidly lead to eradication of human diseases. This has not happened. Despite a wide range of forensic analyses and application of more technologic advances, the path to success remains elusive.

A common thread to these failures is the focus on controlling complex biologic networks and systems. Candidate agents are directed at specific targets believed to be critical to a particular disease process. Is it possible that this approach is inherently doomed to fail; that complex biologic systems adapt to focused interventions and have intrinsic work arounds? What if the path to success were within the body's own cells, and instead of our relentless pursuit to prove mechanisms and control processes we hardly understand, we took a facilitatory role, creating an environment that permits the body's cells to heal and repair itself, thus overcoming the disease?

Clinical observations and trials using cell therapy support the view that the emerging technology with greatest promise may be the biotechnology within us. Even without understanding precise mechanisms of action, which is rare even for currently marketed small molecules, perhaps unleashing "intrinsic biotechnology" is the path towards conquering disease. This approach appears ripe for success, and lessons from interventions with a view to providing angiogenesis and restoring normal immune balance will be presented.
1:55 HSV Vectors and the Treatment of Chronic Pain

Joseph Glorioso III
Professor of Microbiology & Molecular Genetics,
University of Pittsburgh, School of Medicine
Founder & Scientific Advisor
NuvoVec srl.
Chronic pain represents a major cause of morbidity, significantly impairing quality of life and imposing a substantial financial and healthcare burden. The wide distribution of a limited range of neurotransmitters, receptors, and ion channels in the nervous system makes it difficult to selectively target pain-related pathways using drugs that are administered systemically with the potential for side affects that limit both dose and effectiveness. Our group and others have used HSV-based vectors to deliver inhibitory neurotransmitters or gene products that attenuate the action of pronociceptive molecules in primary afferents thereby blocking nocisponsive neurotransmission in a variety of pre-clinical pain models and more recently in patients. Strides in vector development for pain gene therapy should improve patient application. These include (i) the creation of a highly defective vector platform that only expresses the pain relieving transgene product, (ii) the development of vector targeting strategies that selectively provide transgene expression in subpopulations of sensory neurons contributing to chronic pain activity thereby maximizing pain treatment and (iii) the development of a drug-regulated gene therapy system that allows continuous, long-term expression of a neuronal silencing transgene product whose silencing activity is completely dependent on the systemic administration of an activating drug. Progress in the development of these new advances in pain gene therapy technologies will be described.
2:20 The Emergence of Gene Therapy Gene and Future Therapies

Ian Phillips
Director, Center for Rare Disease Therapies
Keck Graduate Institute of Applied Life Sciences
The latest advances in gene therapy indicate that gene therapy is a viable new therapy for multiple diseases. In December 2011NEJM published results of a successful hemophilia B gene therapy using adeno_associated virus ( AAV). In November 2012, the European Medicines Agency approved Glybera® the First in Class gene therapy. Glybera® ( UniQure ) is built on an AAV platform. It is for treatment of familial homozygous hypercholesterolemia (HoFH). In January 2013 Kynamro (Mipomersen) (Sanofi /Genzyme /Isis) antisense inhibitor of apo B-100 mRNA for apolipoprotein to lower LDL was approved by the FDA. Another Antisense for Duchenne Muscular Dystrophy ( Sarepta-eteplirsen ) is in trials. In July 2013 two papers in Science reported successful gene therapy in two rare disease with modified retroviruses safe for human use without risk of cancer. The 2013 National Clinical Research Award was made to the Univ Penn team that developed AAV RPE65 gene therapy for Leber’s Congenital Amaurosis (LCA) blindness. The major gene therapy platforms are AAV, Lentivirus, and antisense. AAV is a reliable, safe, long lasting, platform for delivery of a gene in gene therapy. Lentivirus is being tested in adrenoleukodystrophy( Bluebird Bio ) AAV may be a one shot cure, whereas antisense can be given in monthly injections. Which diseases qualify for gene therapy? So far, monogenetic diseases for which there is no alternative therapy or only a very expensive one with problems. In future gene therapy could be used for non rare disease and have a huge world wide market.
2:45 Harnessing the Potential of iPSC Technology

Dhruv Sareen
Director, Cedars-Sinai's Induced Pluripotent Stem Cell Core
Cedars Sinai Medical Center
Human induced pluripotent stem cell (iPS) cell technology provides an excellent source of inaccessible patient tissues (neurons or cardiac cells). As such they are also being introduced as components of modern drug discovery programs in research laboratories. Therefore, developing high-content screening tools with patient iPS cells can address a significant bottleneck in drug development, i.e., they can reproducibly provide an unlimited supply of physiologically-relevant and functional human cells for predictive high-content cellular assays with the advantage of patient-specific genetics. Dr. Sareen will highlight iPS cells pluripotent stem and their neuronal derivatives to discuss:

• How to utilize pluripotent stem cells in disease modeling and drug discovery
• Amenable platforms for high-content screening with iPSC-derived cells
• The challenges and solutions for translating iPSC-derivatives from lab-scale to high-content and high-throughput
• How to develop predictive cellular assays that closely simulates disease phenotype

Attendees will leave this talk with ideas and tools needed to develop the next generation of drug discovery programs by incorporating high content screening modalities on biologically relevant patient-specific stem cells and neurons.
3:10 CMC Supporting Early to Late Phase Clinical Development for an AAV Investigational Product

Fraser Wright
Director, Clinical Vector Core Center for Cellular and Molecular Therapeutics
Children's Hospital of Philadelphia
Associate Professor, Pathology and Lab Medicine
University of Pennsylvania Perelman School of Medicine
Recombinant gene transfer vectors based on adeno-associated viruses (AAV) continue to demonstrate great promise to meet unmet medical needs for serious diseases. Key recent milestones, including the successful licensure of a recombinant AAV based product, as well as emerging positive safety and efficacy results using AAV vectors in clinical development, illustrate the continuing emergence of this AAV based gene transfer vectors as an important new class of therapeutics. This presentation will describe strategies we have developed for successful Chemistry, Manufacturing and Controls (CMC) for an AAV-based investigational product for a Phase III clinical trial for Leber Congenital Amaurosis. Benefits of the talk will include learning about: challenges for PhIII clinical trials from the perspective of vector design, manufacturing and quality; insight into CMC challenges for an emerging class of therapeutics; considerations for gene therapy product licensure; safety and efficacy of gene therapy in clinical trials.
3:35 Afternoon Networking Break
4:05 Translational Development of Retroviral Replicating Vectors (RRV)

Douglas Jolly
Executive Vice President, Research & Pharmaceutical Development
  Retroviral replicating vectors (RRV) can deliver therapeutic genes efficiently and selectively to tumors by preferentially infecting cancer cells, without causing immediate cell lysis. Toca 511 (vocimagene amiretrorepvec) is an RRV encoding a codon-optimize, heat stabilized yeast cytosine deaminase (CD) gene. The CD enzyme converts the prodrug 5-FC (5-fluorocytosine) to the anticancer drug 5-FU (5-fluorouracil) in the infected cancer cells. Before moving this investigational therapy into clinical trials for recurrent High Grade Glioma (rHGG, primary brain cancer), we improved the vector, the CD gene, the prodrug, the physical delivery systems and vector manufacturing. Toca 511 exhibits a high degree of tumor specificity, without significant infection of normal cells in several animal models, and this property appears to be replicated in human trial subjects. The specificity can be attributed to a mixture of the absolute requirement for replicating cells to achieve productive RRV infection, local tumor-induced immune suppression and defects in the tumors’ IFN signaling pathways. In animal models, durable anti-tumor responses are associated with the development of anti-tumor immunity after treatment-mediated tumor lysis, Toca 511 in combination with Toca FC (an extended-release formulation of 5-FC) is currently in Phase I dose-escalation clinical trials for rHGG patients, administered in three ways: intra-tumoral injection; injection into the resection cavity; and intravenously ( NCT01156584, NCT01470794, NCT01985256). Cumulatively over 68 patients have been treated without dose limiting toxicity and with evidence of biological and clinical activity in some patients.
4:30 How to Stealth the Immune System: Efficient Organ-Specific Surgical Techniques for Cardiac Gene Delivery

Charles R. Bridges
Professor & Chairman, Cardiovascular Surgery
Sanger Heart & Vascular Institute
Carolinas HealthCare System
  Successful gene therapy for heart failure will require: 1) a transgene with potential for therapeutic efficacy; 2) a vector with long term gene expression and 3) a delivery method that efficiently transduces cardiac myocytes in situ in humans.  Transgenes with therapeutic efficacy have been identified and appropriate viral vectors  exist.  What is lacking clinically is an efficient clinical delivery method.  Current delivery methods are fraught with limitations: 1) intramuscular delivery has an upper limit of about 1 x 1013 genome copies  due to AAV concentration limits and the volume of the cardiac extracellular compartment.   A strong innate and subsequently adaptive immune response to the viral capsid is often elicited; 2) intracoronary delivery has never been shown to transduce more than 1% of myocytes in a large animal model; 3) intravenous delivery would require economically unfeasible doses of vector  with a small minority of cardiac myocytes likely to be transduced.  Furthermore, all of these approaches result in the majority of vector delivery to the reticuloendothelial system, facilitating a T-cell mediated immune response.  Finally, patients with preexisting antibody to AAV must be excluded from trials.  In contrast, minimally invasive surgical delivery allows for transduction of the majority of myocytes in situ and by allowing for the removal of blood components prior to delivery as well as by limiting vector delivery to the heart there is the potential for: 1) dramatic therapeutic efficacy; 2) avoidance of a T-cell mediated immune response and 3) offering therapy to patients with pre-existing immunity against AAV.
1. Highlight the current status of clinical trials for heart failure
2. Underscore the importance of efficient  vector delivery to achieving effective heart failure gene therapy
3. Highlight the importance of the T-cell mediated immune response in AAV-mediated gene therapy
4. Gain familiarity with a promising preclinical surgical approach to heart failure gene therapy that may have applications
    for both ischemic and genetic cardiomyopathy
4:55 Advances in Nuclease-mediated Gene Targeting

Dana Carroll
Professor of Biochemistry
University of Utah
In the past decade or so, there have been amazing developments in the area of nuclease-mediated gene targeting. First with zinc-finger nucleases (ZFNs) and more recently with TALENs and CRISPR/Cas, it is possible to make very specific, targeted double-strand breaks at essentially any arbitrarily chosen genomic sequence. Repair of such breaks leads to local mutagenesis, and in the presence of an engineered donor DNA, to targeted gene editing. These reagents have been applied successfully to genome manipulations in more than 40 species of animals and plants. Features of each of these platforms for precision genome engineering will be described, including design, delivery, outcomes and efficiency.

Applications of these tools to cell and gene therapy include the relatively facile production of animal models and therapeutic correction of disease alleles. Current applications of nuclease-based gene therapy are typically envisioned as ex vivo treatments. Prospects for in vivo treatment face the same issues regarding effective delivery as do other gene therapy approaches.
5:20 Better Manufacturing Practice for Cell Therapies

Kevin Murray
The Xvivo Barrier Isolator reduces risk and provides superior process control for the culture, processing, and expansion of cell-based therapeutics. Total isolation protects the cells from possible contamination, the people from viral vectors, prions…as well as allow for the optimization of the cell environment. Critical cell environmental factors such as temperature, RH, CO2 and O2 can be controlled, monitored and uninterrupted throughout the entire cell production process. Dynamic incubation options allow for adjustments in incubation conditions which keep up with the changing needs of dynamic cell cultures. Superior process control results in a higher quality cell product and more consistent results for your entire protocol.
  [Oral Presentations from Exemplary Submitted Abstracts]
5:45 Isolation and Characterization of a Novel Population of Early Lineage Adult (ELA) Stem Cells

Colin D. White
Chief Scientific Officer
Parcell Laboratories
Synovial fluid from osteoarthritic knees (SF) has for some time been recognized as a rich source of adult stem cells (ASCs), and several studies have documented SF-derived ASC isolation and characterization. Previous immunophenotype analyses reveal that each cell population isolated from SF to date expresses a surface marker profile that includes positivity for at least some of CD13, CD44, CD73, CD90 (Thy-1), and/or CD105 (endoglin/SH2), suggesting that these cells may be classed as either mesenchymal stem/progenitor cells or multipotent adult progenitor cells, a subset of the MSC population. For the first time, we report here the isolation and characterization of a novel population of SF-derived ASCs, which we have termed Early Lineage Adult (ELA) Stem Cells. ELA cells do not detectably express CD34, CD44, CD45, CD73, CD90, CD105, and MHC Class I, but do express genes that are indicative of stemness including OCT4A, NANOG, and REX1. In vitro studies reveal that ELA cells differentiate into tissues of ectodermal, mesodermal, and endodermal origins, and in vivo studies demonstrate that ELA cells harbor a significant osteogenic differentiation capacity. Clinically, an ELA cell-based therapy has been developed and used commercially in approximately 3500 surgical procedures for spinal fusion, and a retrospective chart review of treated patients revealed promising results, with detectable fusion as early as 6 months post-surgery and no attributable adverse events. The product is processed using a centrifugation-based procedure, cryopreserved (in CryoStor CS10), and delivered frozen to the operating room for surgical implantation. As ELA cells appear to proliferate extensively without loss of differentiation potential, and we have demonstrated that ELA cell-based therapies designed for clinical use can be produced, we suggest that ELA cells likely represent a novel source of stem cells for the potential treatment of numerous diseases.
6:05 Networking Reception & Poster Session
Day 1 Day 2
Day 2 - Friday, February 21, 2014
7:30 Continental Breakfast
Emerging Technologies (continued)
Moderator: Noriyuki Kasahara, UCLA
8:00 Gene Delivery with Ultrasound and Acoustically Active Carriers

Evan Unger
Co-Director, Cancer Imaging Program
Professor of Radiology
University of Arizona Cancer Center
Microbubbles such as Definity® (developed by the speaker), phospholipid-coated perfluoropropane microbubbles, are FDA approved as ultrasound contrast agents. Microbubbles have been used in clinical trials as therapeutic agents (e.g. for treatment of stroke to restore blood flow) as they cavitate with relatively high-energy ultrasound, but still within the spectrum of power levels allowed by the FDA. Microbubbles can also be used with ultrasound for gene delivery. Microbubbles + genes can be delivered IV and site-specific gene delivery afforded by applying ultrasound to the target tissue. Microbubbles can be prepared to bind genes and also to target cell-specific epitopes. We have prepared nanocomposites containing a fluorocarbon nanobubble targeting E-selectin and the target cells internalize the nanocomposites. Fluorocarbon emulsions containing dodecafluoropentane (DDFPe), with a boiling point = 29oC, also called NVX-108, is currently under development as an oxygen therapeutic by NuvOx. DDFPe carries over 100 x > more oxygen than higher molecular weight, high boiling point fluorocarbons. DDFPe is also responsive to ultrasound and can be used for site-specific gene delivery.

Acoustically active carriers offer a novel non-viral platform technology for site-specific gene delivery.
Clinical Trials & Research
Moderator: Noriyuki Kasahara, UCLA
8:25 Clinical Development of an IL-12 Gene Therapeutic for the Treatment of Peritoneally Metastasized Cancers

Khursheed Anwer
President & Chief Scientic Officer
This presentation describes the clinical development of EGEN-001, a novel immunotherapeutic agent for local treatment of peritoneally metastasized epithelial ovarian cancer. Peritoneal metastasis of ovarian cancer is a local disease and a primary cause of mortality in ovarian cancer patients. The current treatments are based on cytotoxic drugs which are administered systemically and are practically ineffective with serious toxicities, justifying the need for therapies that are novel and have good scientific and clinical rationale. EGEN-001 is composed of an interleukin-12 (IL-12) gene expression plasmid and a biocompatible delivery lipopolymer, PEG-PEI-Cholesterol (PPC). This cytokine expression of IL-12 by EGEN-001 is designed to increase the local concentration of IL-12, a potent anti-cancer cytokine that stimulates the immune system to aid in fighting cancer growth and metastases. EGEN-001 has distinct advantages over current approaches to cancer therapy. Unlike chemotherapy and antibody therapy, EGEN-001 does not cause hematological, neurological or liver toxicity. In comparison to IL-12 protein therapy, EGEN-001 increases IL-12 concentrations locally at tumor site in the peritoneal cavity with minimal escape into the systemic circulation. Both preclinical and clinical studies have confirmed that the distribution of IL-12 plasmid and production of IL-12-mediated cytokines following intraperitoneal delivery of EGEN-001 is primarily at the site of administration. The safety and biological activity of escalating doses of EGEN-001 alone or in combination with standard chemotherapy has been or is being investigated following intraperitoneal administration in chemotherapy sensitive or chemotherapy resistant ovarian cancer patients in different human clinical trials. The drug safety, anti-tumor activity and biological activity results from various clinical trials of EEGN-001 intraperitoneal will be discussed in this presentation. In addition, the cGMP manufacturing, scale up and quality control of EGEN-001 clinical product will also be discussed. In summary, EGEN-001 is a novel anticancer therapeutic that relies on increasing local concentrations of a powerful anticancer cytokine IL-12 that works by stimulating the patient's immune system against cancer. A distinct advantage of EGEN-001 over current treatment methods (chemotherapy & antibodies) is that it works by a novel mechanism, does not have systemic toxicity, and can be administered safely for a number of treatments. The available safety and activity data from human clinical trials warrant continued development of EGEN-001 as a local immunotherapy for the treatment of recurrent ovarian cancer, a disease of high unmet need.
8:50 The Tortoise and the Hare – Keeping Pace with the Tortoise (and Winning the Race Together)

Sean O'Bryan
Associate Director, Regulatory Affairs
Cell therapies have historically outpaced the regulatory bodies that develop framework for such therapies. In fact, until recently, in the EU some cell therapies have long been commercialized without any requirements for marketing authorization. This presentation will use Genzyme’s MACITM (matrix applied characterized cultured autologous chondrocytes) product as a case study to highlight the mechanisms of regulatory change, Agency collaboration, and business adaptation toward navigating and succeeding within the fluid landscape toward an internationally harmonized regulated field.
9:15 Manufacturing and Clinical Development of MultiStem®, a Drug-like Cell Therapeutic

John Harrington
Executive Vice President & Chief Scientific Officer
Cell therapy is an emerging area of product development in the pharmaceutical and biotechnology industries. Several dozen companies have initiated clinical studies over the past 5 to 10 years to investigate novel cell products in a variety of clinical indications, and large pharmaceutical companies are beginning to establish internal capabilities and external partnerships. In this presentation, the key aspects of developing a cell therapy product will be discussed, using MultiStem® as a case study. A particular focus will be placed on describing the manufacturing strategy for producing the clinical product, evaluating mechanism of action in preclinical models, and assessing the safety and efficacy of MultiStem® in multiple clinical trials. Similarities and differences between recombinant proteins/antibodies and cell therapy development will be highlighted.

Bullet Points:
• Case Study for development of a cell therapeutic
• Manufacturing strategy for producing a cell therapy product
• Understanding mechanism of action and selecting clinical indications for investigation in humans
• Manufacturing, pharmacology, biodistribution, PK/PD, and toxicology of cell therapeutics
9:40 Lessons Learned in Initiating the Largest Gene Therapy Trial in Advanced Heart Failure

Jeff Rudy
Vice President, Clinical Operations
In 2012, Celladon Corporation launched the largest gene therapy trial, in terms of the number of investigative sites and countries, of MYDICAR (AAV1/SERCA2a) for the treatment of advanced heart failure. Celladon Corporation is a clinical-stage biotechnology company applying its leadership position in the field of calcium dysregulation targeting SERCA enzymes to develop novel therapies that may transform the lives of patients in a number of diseases with tremendous unmet medical needs. MYDICAR targets SERCA2a, which is an enzyme that becomes deficient in patients with heart failure. This talk will cover the key lessons learned in study start-up of a phase 2b trial in over 60 investigative centers in Belgium, Denmark, Germany, Hungary, Israel, The Netherlands, Poland, Sweden, UK and USA. Potential benefits of the talk to attendees include: gaining a better understanding of additional resources, above and beyond the resources of an average clinical trial, needed from the company to sites, clinical research organization and regulators (competent authority, environmental ministry regulating GMO release, ethics committee, local biosafety committee); and appreciation for longer regulatory timelines and implications in overall strategy and planning of a gene therapy study.
10:05 Morning Networking Break
10:35 A Small Molecule Approach for Relieving Lentiviral Vector Transduction Resistance in Human and Mouse Hematopoietic Stem Cells

Bruce Torbett
Associate Professor
Director, The Molecular Basis of Viral Pathogenesis Fellowship Program
Co-Director, CFAR Protein Expression and Proteomics Core
The Scripps Research Institute
Transplantation of genetically modified hematopoietic stem cells is a promising therapeutic strategy for genetic diseases, HIV, and cancer. However, a barrier for clinical hematopoietic stem cell gene therapy is the limited efficiency of gene delivery via lentiviral vectors into quiescent, non-cycling hematopoietic stem cells (HSCs). Our studies on HSC resistance to lentiviral vector entry and integration have uncovered that rapamycin, an inducer of autophagy through allosteric inhibition of the mammalian target of rapamycin (mTOR) complexes, facilitates highly efficient lentiviral transduction of mouse and human HSCs. Mouse and human HSCs transplant studies in mice have demonstrated that rapamycin treatment enhances both the frequency of HSCs transduced by lentiviral vectors as well as the number of vector copies per cell. Our findings will be discussed in regards to hematopoietic lineages transduced with lentiviral vectors, the rapamycin-mediated transduction mechanisms, HSC lentiviral vector integration profiles, and potential gene therapy applications.
11:00 Ex-Vivo Engineering of Human Hematopoietic Stem Cells: Gene Therapy Towards a Cure for HIV

David DiGiusto
Research Professor, Virology
Director, Laboratory for Cellular Medicine
Beckman Research Institute of the City of Hope
Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected RNA-based HIV-1 inhibitors in the CD4+ cells derived from GM-HSPC will protect them from HIV-1 infection and results in a sufficient immune repertoire to control HIV-1 viremia, potentially resulting in a functional cure for HIV-1/AIDS. Additionally, it is possible that the subset of protected T cells will also be able to facilitate the immune-based elimination of latently infected cells if they can be activated to express viral antigens. Thus, a single dose of disease resistant GM-HSPC could provide an effective treatment for HIV-1+ patients who require (or desire) an alternative to lifelong antiretroviral chemotherapy. We describe herein the results from our pilot clinical studies in HIV-1 patients and our strategies to develop second generation vectors and clinical strategies for HIV-1+ patients with malignancy who require ablative chemotherapy as part of treatment and others without malignancy. Important progress in genetic modification of stem cells, development of second generation anti-viral vectors and pre-clinical animal modeling will be discussed
11:25 Neural Stem Cell-Mediated Targeted Cancer Therapies: Clinical Trial Development

Karen S. Aboody
Professor, Neurosciences
City of Hope National Medical Center & Beckman Research Institute
CSO & Director
TheraBiologics, Inc
  Human neural stem cells (NSCs) are inherently tumor-tropic, localizing to tumor foci following intracerebral or intravenous administration in preclinical models of primary and secondary brain tumors, breast carcinoma, and neuroblastoma. These NSCs can be engineered to express numerous therapeutic agents, making them attractive drug delivery vehicles. By concentrating therapy selectively at the tumor sites, toxicity to normal tissues and associated side effects are minimized. We recently completed a first-in-human safety study using genetically modified NSCs for tumor selective enzyme/prodrug therapy in recurrent glioma patients. Cytosine Deaminase expressing NSCs were administered into the resection cavity or biopsy site, followed by oral prodrug 5-Fluorocytosine (5-FC). This trial also included first-in-human use of Feraheme labeling of NSCs for MRI tracking. Safety, feasibility, and proof of concept of localized conversion of 5-FC to the active chemotherapeutic 5-Flurouracil (5-FU) was demonstrated. No significant immune response was detected following one round of treatment.

This NSC platform technology is being developed for several upcoming phase I cancer trials and includes intracerebral administration of carboxylesterase (CE)-secreting NSCs, that locally convert irinotecan (CPT-11) to the potent topoisomerase inhibitor SN-38, for brain tumor patients. This same CE-NSC product is being developed for intravenous administration to treat pediatric patients with metastatic neuroblastoma – phase I trials are planned for 2017. A third planned phase I trial for newly diagnosed glioma patients uses NSCs as a platform for delivery of a conditionally replication competent oncolytic virus. These initial clinical studies will lay the foundation for development of additional NSC applications – targeting an array of therapeutic agents to invasive cancers.

Supported by: NCI 1R21 CA137639-01A1, California Institute for Regenerative Medicine DR1-01421, NIH-NINDS U01-NS082328, NIH-NINDS U01-NS069997. Disclosure: KSA is CSO & Director of TheraBiologics, Inc.
11:50 Interim Report on Phase 1 Ascending Dose Trials of a Retroviral Replicating Vector (Toca 511) in Patients with Recurrent High Grade Glioma

Noriyuki Kasahara
Professor, Medicine and Molecular & Medical Pharmacology
Director, JCCC Vector Shared Resource & CURE Vector Core Facility
University of California Los Angeles
  We are conducting investigational ascending dose trials in patients with High Grade Glioma (HGG, NCT01156584 and NCT01470794), using a retroviral replicating vector (Toca 511, vocimagene amiretrorepvec). Toca 511 encodes an optimized yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) to the anticancer drug 5-FU in infected tumors. In these studies Toca 511 is administered once, followed by repeat courses of oral Toca FC (an extended-release formulation of 5-FC). One trial employs direct intra-tumoral injection of Toca 511 and the other administration into the resection cavity wall after resection of a recurrent tumor. Over 30 patients have been treated in each of these dose escalation trials with 6 and 5 viral dose levels respectively studied to date. Treatment at all dose levels has been well tolerated. Post-treatment resection in some patients showed viral protein and DNA and RNA sequences including the CD protein and gene, suggesting viral spread and persistence. At higher Toca 511 doses, MRI changes consistent with tumor regression were observed post-Toca FC dosing and clinical improvements were also observed in some patients. Survival data at 6 months and at 1 year compared to historical data is supportive of antitumor activity. Completion of these studies is planned, including further dose escalation of Toca 511 and of Toca FC.
12:15 Lunch Provided by GTC
Strategies for Commercialization
Moderator: Noriyuki Kasahara, UCLA
1:15 Case Study: Leveraging a CDMO to Optimize the Financial and Operational Efficiency of Emerging Cell Therapy Business

Sanjin Zvonic
Technology & Business Development
Progenitor Cell Therapy
This talk will highlight the shifting nature of resource demands and distribution during commercialization of cell therapy products, and discuss how a contract development and manufacturing organization can be leveraged by the developers to meet these demands in a time and cost-efficient manner, while providing risk mitigation. Additionally, a case study will be presented illustrating the discussed concepts.
1:40 Best Practices in Stability/Biopreservation for Cell & Tissue Bioprocessing, Clinical Development, and Patient Delivery

Aby J. Mathew
Senior Vice President & Chief Technology Officer
BioLife Solutions, Inc.
  Cellular therapies and regenerative medicine utilize cell and tissue products sourced from blood, bone marrow, and various tissues. The clinical and commercial success of these products is potentially impacted by stability limitations, which include transport of the source material and biopreservation of the final cell or tissue product (either frozen or non-frozen). Traditional home-brew reagent cocktails (including serum) utilized for biopreservation are a point of risk within a GMP clinical manufacturing process. This discussion will offer methods for optimizing stability/shelf-life, and explore the critical role and impact of biopreservation in the development and commercialization of regenerative medicine products. Topics include best practices in optimizing biopreservation workflow, including transportation and storage of source material and final dose, intermediate manufacturing process hold steps, and evaluation, selection, and validation of ancillary and excipient reagents.
2:05 Manufacturing Natural Killer Cells for Adoptive Immunotherapy- Beyond the Boutique

Dean Lee
Associate Professor, Division of Pediatrics, Cell Therapy Section
University of Texas MD Anderson Cancer Center
Natural killer cells are large granular lymphocytes of the innate immune system first described four decades ago for their ability to recognize and kill target cells a priori- without prior experience of the target- in a manner that is both antigen and MHC-unrestricted. Recent advances in understanding their biology have allowed greater insight in the role of NK cells in controlling cancer and viral diseases. The ability to generate clinical-grade NK cell products of sufficient purity, number, and function has only recently allowed adoptive NK cell immunotherapy to be pursued in clinical trials, including the approach developed at MD Anderson Cancer Center which has proven effective for expanding NK cells to large numbers from peripheral blood, cord blood, and induced pluripotent stem cells. In the context of these approaches we will discuss the current obstacles and potential solutions for commercialization:

• What are the clinical-scale methods currently in use for generating therapeutic NK cells?
   Potential advantages or disadvantages
• What are the hurdles to manufacturing at scale?
• Should cryopreservation be pursued?
• Can we identify “ideal” donors?
• Should we pursue centralized or distributed manufacturing strategies?
• Other potential strategies to enable off-the-shelf products.

James McLaughlin
Venture Associate
Third Rock Ventures
2:55 Conference Concludes
Day 1 Day 2
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