4th cell therapy conference : manufacturing and testing of...

4th Cell Therapy Conference : Manufacturing and Testing of Pluripotent Stem Cells

June 5-6, 2018Los Angeles, California

With support from and in collaboration with The California Institute for Regenerative Medicine (CIRM)

Sponsors

IABS - Rue de la Vallée, 3 - 1204 Geneva - SwitzerlandTel : +41 22 301 10 36 - Fax : +41 22 301 10 37 - www.iabs.org


June 5-6, 2018 - Los Angeles, California

Scientific Committee

About the Conference

Professor Glyn Stacey - Chair, Scientific Committee; International Stem Cell Banking Initiative, United KingdomDr. Abla Creasey - California Institute for Regenerative Medicine (CIRM)Dr. Stephen Lin - California Institute for Regenerative Medicine (CIRM)Dr Anthony Lubiniecki - International Alliance for Biological Standardization (IABS), U.S.A.Dr. Ivana Knezevic - World Health Organisation (WHO), SwitzerlandDr. Yoji Sato - National Institute of Health Sciences, JapanProfessor Jean-Hugues Trouvin - University Paris Descartes, School of Pharmacy, FranceDr. Elwyn Griffiths - International Alliance for Biological Standardization (IABS), United KingdomDr. Kathryn Zoon - Emeritus, National Institutes of Health, U.S.A. Dr. Robert Deans - BlueRock Therapeutics, Cambridge, Massachusetts, U.S.A.Dr. Kathleen Francissen - Genentech, U.S.A.Dr. Thorsten Gorba - IQVIA, Stem Cell Center, U.S.A.Dr Karin Hoogendoorn - Leiden University Medical Center, The NetherlandsProfessor Krishnendu Roy - Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M), Georgia Tech University, U.S.A.

Objectives and Expected Outcomes

The 2018 Cell Therapy conference will identify key unresolved issues that need to be addressed for the manufacture and testing of pluripotent stem cell-based therapies and provide scientific consensus on selected aspects to inform the drafting of future national and international guidance. The meeting will bring together representatives from industry, academia, health services and regulatory bodies.

The overall goal of the conference is to provide the target audience with an appreciation of the impor-tance of a well-controlled manufacturing process for cell therapies that are in development, and to highlight specific areas that should be considered during early product development in order to avoid issues in later stages. The target audience includes those individuals and organizations actively pursuing research and development of cell therapies with the intent of achieving pluripotent stem cell therapy products that meets regulatory requirements for approval, thus becoming generally available to treat patients with unmet medical needs.

We will build on previous meetings that generally addressed broader themes of cell therapy studies and manufacturing issues. In addition to reviewing information on the state-of-the-art and recently generated data, this conference ill drill down to key practical issues facing cell therapy developers and regulators to expedite the safe and efficient introduction of new treatments for important diseases where unmet medical needs exist.

More specifically, the conference is expected to provide a basis for new and/or additional guidance on regulatory expectations for developing acceptable pluripotent cell therapy products including testing requirements during manufacture. Concrete conclusions and recommendations will be important out-comes, which are expected to stimulate the field to move forward in a transparent and coordinated manner.




Scientific Program




Monday, June 4, 2018

WELCOME RECEPTION 6:00 pm - 8:00 pm

Hosted by STEMCELL Technologies

Spotlight on Standards DevelopmentProf. Glyn Stacey

The International Stem Cell Banking Initiative. Consensus standards for hPSCs for clinical application.

Dr. Anthony Ratcliffe, ARM-SCB/ASTMThe ARM-Standard Coordinating Body and ASTM.

Dr. Tatsuo HekiIndustrialization of regenerative medicine: standards are the key.

Dr. Sheng Lin-GibsonNIST standardisation programmes

Day 1 Tuesday, June 5, 20188:00 am Registration & Welcome Coffee

8:30 am Welcome Dr. Anthony Lubiniecki, International Alliance for Biological Standardization (IABS), U.S.A. Dr. Abla Creasey, California Institute for Regenerative Medicine (CIRM) San Francisco, California, U.S.A.

8:45 am Highlights from Cell Therapy 2014 - 2015 - 2016 Prof. Takao Hayakawa, Kindai University, Tokyo, Japan Prof. Glyn Stacey, Chair, Scientific Committee; International Stem Cell Banking Initiative, United Kingdom

Session 1 - Learning from the current pluripotent space and the development of international standards

Case studies in the challenges of pluripotent stem cell development Chairs: Dr. Thorsten Gorba, IQVIA Stem Cell Center, San Diego, California, U.S.A.

Dr. Kapil Bharti, National Eye Institute (NEI) / National Institutes of Health, Bethesda, Maryland, U.S.A.

9:00 am Introduction to Session 1 - Part I by the Chairs

9:05 am Experiences in taking human embryonic stem cells to clinic Dr. Edward Wirth, Asterias Biotherapeutics, Fremont, California, U.S.A.

9:25 am Taking neural progenitors and iPSC cells to the clinic for ALS and Retinitis Pigmentosa: two case reports Prof. Clive Svendsen, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.

9:45 am IND-enabling In vitro and In vivo functional authentication of AMD-patient derived clinical-grade iPSC-RPE tissue Dr. Kapil Bharti, National Eye Institute (NEI) / National Institutes of Health, Bethesda, Maryland, U.S.A.

10:05 am Panel discussion Dr. Thorsten Gorba, IQVIA Stem Cell Center, San Diego, California, U.S.A. Dr. Edward Wirth, Asterias Biotherapeutics, Fremont, California, U.S.A. Prof. Clive Svendsen, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A. Dr. Kapil Bharti, National Eye Institute (NEI) / National Institutes of Health, Bethesda, Maryland, U.S.A. Dr. Shin Kawamata, Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan

Topics for discussion : • What challenges have the developers experienced in relation to using pluripotent stem cells as manufacturing cell substrates ?

• What experiences can be anticipated in the transition from one cell substrate type to another for the same indication and how can developers best manage the challenge of demonstrating comparability and scale up ?

• What have been the major learning outcomes over the last ten years experience of taking pluripotent stem cells to therapy ?

• What are the key differences between developing and standardising autologous versus allogenic cell therapies ?



Scientific Program


Scientific Program

Day 1 Tuesday, June 5, 2018Session 1 - con’t.

10:45 am Coffee break

Learning from international standardisation Chairs: Dr. Kathryn Zoon, Emeritus, National Institutes of Health, Bethesda, Maryland, U.S.A.

11:15 am Introduction to Session 1 - Part 2 by the Chair

11:20 am Historical perspective: the importance of early regulatory guidance for biotherapeutics Dr. Elwyn Griffiths, International Alliance for Biological Standardization (IABS), United Kingdom

11:40 am WHO standards for cell therapies: key issues in defining quality, safety and efficacy Dr. Ivana Knezevic, World Health Organization, Geneva, Switzerland

12:00 pm Panel discussion – International regulatory landscape Dr. Kathryn Zoon, Emeritus, National Institutes of Health, Bethesda, Maryland, U.S.A. Dr. Elwyn Griffiths, International Alliance for Biological Standardization (IABS), United Kingdom Dr. Ivana Knezevic, World Health Organization, Geneva, Switzerland Dr. Edward Wirth, Asterias Biotherapeutics, Fremont, California, U.S.A. Prof. Clive Svendsen, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A. Dr. Thorsten Gorba, IQVIA Stem Cell Center, San Diego, California, U.S.A. Dr. Kapil Bharti, National Eye Institute (NEI) / National Institutes of Health, Bethesda, Maryland, U.S.A. Dr. Steven S. Oh, Center for Biologics Evaluation and Research, U.S. FDA, Silver Spring, Maryland Prof. Bao Zhu Yuan, National Institutes for Food and Drug Control, Beijing, China Dr. Gerald G. Schumann, Paul-Ehrlich-Institut, Langen, Germany Dr Francisca Agbanyo, Health Canada, Ottawa, Canada

Questions for each regulator : • What guidances specific to pluripotent stem cells do you have available?• What are the challenges in meeting the regulation for pluripotent stem cell based products?• What need do you perceive for physical standards/reference materials in this area?

General questions : • Is there a need for new guidance and standards.• Are there any special issues relating to off-trial treatments such as Hospital Exemptions/ Special arrangements?• Any other challenges for the broader scope of cell-based medicines?

12:45 am Lunch




Scientific Program

Day 1 Tuesday, June 5, 2018

Session 2 - Bioanalytics and comparability (non-clinical and quality control)Chairs: Dr. Kathleen Francissen, Genentech, South San Francisco, U.S.A.

Dr. Steven S. Oh, Center for Biologics Evaluation and Research, U.S. FDA, Silver Spring, Maryland, U.S.A.

1:30 pm Introduction to Session 2 by the Chairs

1:35 pm Cellular product manufacturing and comparability considerations Dr. Steven S. Oh, Center for Biologics Evaluation and Research, U.S. FDA, Silver Spring, Maryland, U.S.A.

1:55 pm Devising assays and standards for cell therapies Dr. Orla O’Shea, National Institute for Biological Standards and Control-MHRA, Hertfordshire, United Kingdom

2:15 pm Characterization of CAR T cells- autologous vs allogeneic Dr. Shirley Bartido, Cellectis, New York, U.S.A.

2:35 pm Is the product the process? Dr. Stewart Abbot, Fate Therapeutics, La Jolla, California, U.S.A.

2:55 pm Coffee break

3:15 pm Developing predictive assays to assess function and purity of dopaminergic progenitors for treatment of Parkinson’s Disease Dr. Agnete Kirkeby, University of Copenhagen, Denmark; University of Lund, Sweden

3:35 pm Panel discussion - Assay development focusing on characterisation, potency assays and comparability Dr. Kathleen Francissen, Genentech, South San Francisco, U.S.A. Dr. Steven S. Oh, Center for Biologics Evaluation and Research (CBER), U.S. FDA, Silver Spring, Maryland Dr. Orla O’Shea, National Institute for Biological Standards and Control-MHRA, Hertfordshire, United Kingdom Dr. Shirley Bartido, Cellectis, New York, New York, U.S.A. Dr. Stuart Abbot, Fate Therapeutics, La Jolla, California, U.S.A. Dr. Agnete Kirkeby, University of Copenhagen, Denmark; University of Lund, Sweden Karin Hoogendoorn, Leiden University Medical Center, The Netherlands

Topics for discussion:

• What approaches can be used to identify key quality attributes of cell therapy products that could be used to demonstrate comparability?

• Do we need to fundamentally re-think approaches to ensuring product quality consistency?

• In the absence of reference standards, how are system suitability standards for analytical tests generally handled?

• Do we have appropriate definitions for potency, purity and identity for cellular therapies and how should they be applied?

• What should a potency assay seek to demonstrate and do we have good examples?






Scientific Program


4:20 pm Presentation to Dr. John Petricciani, International Alliance for Biological Standardization (IABS), U.S.A. Dr. Ivana Knezevic, World Health Organization (WHO), Geneva, Switzerland Dr. Anthony Lubiniecki, International Alliance for Biological Standardization (IABS), U.S.A. Prof. Glyn Stacey, Chair, Scientific Committee; International Stem Cell Banking Initiative, United Kingdom

4:35 pm End of Day 1

SPOTLIGHT ONDr. David L. DiGiusto,

An Academic Perspective on Cell and Gene Therapy DevelopmentExecutive Director, Stem Cells and Cellular Therapeutics Operations

Stanford Healthcare Senior Research Scientist

Division of Pediatric Stem Cell Transplantation and Regenerative Medicine Stanford University School of Medicine

RECEPTIONHOSTED BY IQVIA STEM CELL CENTER

5:00 pm - 7:00 pm

Day 2 Wednesday, June 6, 2018

Session 3 - Tumorigenicity Testing

In vivo and in vitro methods, including genetic changes: correlations, issues, the way forward Chairs: Mercedes Serabian, U.S. Food & Drug Administration (FDA), Silver Spring, Maryland, U.S.A.

Dr. Yoji Sato, National Institute of Health Sciences, Tokyo, Japan

8:30 am Introduction to Session III by the Chairs 8:35 am Regulatory implications of in vivo tumorigenicity testing

Associate Prof. Björn Carlsson, Medical Products Agency, Uppsala, Sweden

8:55 am Tumorigenicity assessment of stem cell-based therapies: FDA/CBER considerations Mercedes Serabian, U.S. Food & Drug Administration (FDA), Silver Spring, Maryland, U.S.A.

9:15 am Study design considerations for in vivo tumorigenicity assays Dr. Shawna Jackman, Charles River Laboratories, Horsham, Pennsylvania, U.S.A.

9:35 am Imaging technology and biodistribution studies Prof. Christopher Goldring, University of Liverpool, United Kingdom

9:55 am Genetic and epigenetic stability of human pluripotent stem cells Prof. Martin Pera, International Stem Cell Initiative / Jackson Laboratory, Bar Harbor, Maine, U.S.A.

10:15 am Coffee break



Scientific Program


Day 2 Wednesday, June 6, 2018Session 3 - con’t.10:45 am Design and validation of ESC removal in the manufacturing process

Dr. Jane Lebkowski, Regenerative Patch Technologies, Menlo Park, California, U.S.A.

11:05 am Design of In vivo tumorigenicity assays for iPSC-derived cell produce - Lessons from clinical studies in Kobe Dr. Shin Kawamata, Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan

11:25 am HESI CT-TRACS: an international platform for discussions on tracking, circulation and safety of cell therapy products Dr. Yoji Sato, National Institute of Health Sciences, Tokyo, Japan

11:45 am Panel discussion - Strengths and weaknesses of current standards and discussion of several new methods Convener : Dr. Joy Cavagnaro, Access BIO, Boyce, Virginia Mercedes Serabian, U.S. Food & Drug Administration (FDA), Silver Spring, Maryland, U.S.A. Dr. Yoji Sato, National Institute of Health Sciences, Tokyo, Japan Associate Prof. Björn Carlsson, Medical Products Agency, Uppsala, Sweden Dr. Shawna Jackman, Charles River Laboratories, Horsham, Pennsylvania, U.S.A. Prof. Christopher Goldring, University of Liverpool, United Kingdom Prof. Martin Pera, International Stem Cell Initiative / Jackson Laboratory, Bar Harbor, Maine, U.S.A. Dr. Jane Lebkowski, Regenerative Patch Technologies, Seattle, Washington Dr. Shin Kawamata, Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan Dr. Anthony Ratcliffe, LifeNet Health, Virginia Beach, Virginia, U.S.A.

Topics for discussion:

• What are the key pros and cons of the current tumorigenicity assay methods and how relevant are they to development of human disease given the importance of cell microenvironment for tumor development?

• How do we establish and control base lines for genetic stability and tumorigenicity and how can these be related to meaningful assessment of patient safety?

• What impact might the specific cell type have on the development of tumorigenicity assay plat-forms and the controls used?

• What role will in vitro versus in vivo assays have in evaluating tumorigenicity?

• What should be tested, source cells, cell banks, post-manufacture intermediates production or product?

• How can we begin to utilize current knowledge and gain new information to create improved tumorigenicity evaluation assays?

12:40 pm Lunch



Scientific Program


Day 2 Wednesday, June 6, 2018

Session 4 - Manufacture, Storage and Shipment

Chairs: Karin Hoogendoorn, Leiden University Medical Center, The Netherlands Dr. Ivana Knezevic, World Health Organization (WHO), Geneva, Switzerland

1:30 pm Introduction to Session IV by the Chairs

1:35 pm Developing a global haplobank system for clinical-grade induced pluripotent stem cells Dr. Stephen Sullivan, GAiT, United Kingdom

1:55 pm The Universal Cells approach to avoiding immune rejection Dr. Hironobu Kimura, Healios K.K, Tokyo, Japan

2:15 pm Directed differentiation of cGMP compliant human induced pluripotent stem cells into clinically relevant specialized cells from three germ-layers Dr. Behnam Ahmadian Baghbaderani, Emerging Technologies / Lonza , Walkersville, MD, U.S.A.

2:35 pm Large scale GMP manufacturing of individualized autologous directly reprogrammed human neural precursor cells for clinical applications Dr. Jan-Eric Ahlfors, Fortuna Fix, Laval, Canada

2:55 pm Aseptic processing and particulates in cell therapies Dr. Carl Burke, Janssen R&D, Spring House, Pennsylvania.

3:15 pm Coffee break

3:45 pm Preservation and cold chain strategies for cellular therapies Dr. William Shingleton, GE Healthcare, Cambridge, United Kingdom

4:05 pm Enhancing economic reality for cell based medicine through manufacturing optimization Dr. Benjamin Le Quéré, Saint Gobain, Paris, France

4:25 pm Panel discussion - Manufacturing standards, preservation and shipment Karin Hoogendoorn, Leiden University Medical Center, The Netherlands Dr. Ivana Knezevic, World Health Organization (WHO), Geneva, Switzerland Dr. Stephen Sullivan, GAiT, United Kingdom Dr. Behnam Ahmadian Baghbaderani, Emerging Technologies / Lonza , Walkersville, MD, U.S.A. Dr. Jan-Eric Ahlfors, Fortuna Fix, Laval, Canada Dr. Carl Burke, Janssen R&D, Spring House, Pennsylvania, U.S.A. Dr. William Shingleton, GE Healthcare, Cambridge, United Kingdom Dr. Benjamin Le Quéré, Saint Gobain, Paris, France Dr. Tatsuo Heki, Fujifilm Corporation, Tokyo, Japan Dr. Tadaaki Hanatani, CiRA, Kyoto University, Japan Dr. Gary Pigeau, Centre for Commercialization of Regenerative Medicine (CCRM), Ottawa, Canada Dr. Mark Sawicki, Cryoport, Charlotte, North Carolina Dr. Andrew Gaffney, STEMCELL Technologies, Vancouver, Canada



Scientific Program


Day 2 Wednesday, June 6, 2018Session 4 - con’t.

Topics for discussion: • What are the new challenges for development of automated cell culture systems?

• What are the optimal approaches to implementing automated processes?

• How can standards contribute to improved bioprocessing?

• What approach should be taken to setting expiration dates for cryopreserved products?

• What does the developer need to understand about the preservation process?

5:00 pm Summary of key issues and conclusions Prof. Glyn Stacey, Chair, Scientific Committee International Stem Cell Banking Initiative, United Kingdom

5:10 pm End of meeting

Biosketchs & Abstracts



Dr. Stuart Abbot Fate Therapeutics

Dr. Francisca Agbanyo Health Canada

Dr. Jan-Eric Ahlfors Fortuna Fix

Dr. Behnam Ahmadian Baghbaderani Emerging Technologies / Lonza

Dr. Shirley Bartido Cellectis

Dr. Kapil Bharti National Eye Institute / National Institutes of Health

Dr. Carl Burke Janssen R&D

Associate Prof. Björn Carlsson Medical Products Agency

Dr. Joy Cavagnaro Access BIO

Dr. Abla Creasey California Institute for Regenerative Medicine (CIRM)

Dr. Kathleen Francissen Genentech

Dr. Andrew Gaffney STEMCELL Technologies

Prof. Christopher Goldring University of Liverpool

Dr. Thorsten Gorba IQVIA Stem Cell Center

Dr. Elwyn Griffiths International Alliance for Biological Standardization (IABS)

Dr. Tadaaki Hanatani CiRA, University of Kyoto

Prof. Takao Hayakawa Kindai University

Dr. Tatsuo Heki Fujifilm Corporation

Karin Hoogendoorn Leiden University Medical Center

Dr. Shawna Jackman Charles River Laboratories

Dr. Shin Kawamata Foundation for Biomedical Research and Innovation (FBRI)

Dr. Hironobu Kimura Healios K.K.

Dr. Agnete Kirkeby University of Copenhagen; University of Lund

Dr. Ivana Knezevic World Health Organization (WHO)

Dr. Jane Lebkowski Regenerative Patch Technologies

Dr. Benjamin Le Quéré Saint Gobain


Click on the name to view the biosketch or abstract



Dr. Stephen Lin California Institute for Regenerative Medicine (CIRM)

Dr. Anthony Lubiniecki International Alliance for Biological Standardization (IABS)

Dr. Steven Oh U.S. FDA / CBER

Dr. Orla O’Shea National Institute for Biological Standards and Control (NIBSC)

Prof. Martin Pera International Stem Cell Initiative / The Jackson Laboratory

Dr. John Petricciani International Alliance for Biological Standardization (IABS)

Dr. Gary Pigeau Centre for Commercialization of regenerative Medicine (CCRM)

Dr. Anthony Ratcliffe LifeNet Health

Dr. Mark Sawicki Cryoport

Dr. Yoji Sato National Institute of Health Sciences - Japan

Dr. Gerald G. Schumann Paul-Ehrlich-Institut

Mercedes Serabian U.S. FDA / CBER

Dr. William Shingleton GE Healthcare Lifesciences

Prof. Glyn Stacey International Stem Cell Banking Initiative (ISCBI)

Dr. Stephen Sullivan Global Alliance for iPSC Therapies (GAiT)

Dr. Clive Svendsen Cedars-Sinai Medical Center

Prof. Jean-Hugues Trouvin University Paris Descartes, School of Pharmacy

Dr. Edward Wirth Asterias Biotherapeutics

Dr. Bao-Zhu Yuan National Institutes for Food and Drug Control - China

Dr. Kathryn Zoon Emeritus, National Institutes of Health


Click on the name to view the biosketch or abstract

Biosketchs & Abstracts

Biosketch

Stewart E. Abbot, Ph.D. Chief Development OfficerFate Therapeutics3535 General Atomics CourtSan Diego, California, 92121U.S.A.Office: +1 858 875 2969Fax: +1 858 875 [email protected]

Stewart Abbot is the Chief Development Officer at Fate Therapeutics (fatetherapeutics.com). He holds a B.Sc. in Biological Sciences (Edinburgh), M.Sc. in Biomedical Engineering (Glasgow) and Ph.D. in Pathology (London). His academic career focused on basic and translational science initiatives in vascular biology, pharmacology and toxicology. He joined Amersham Biosciences in 2000 and developed Amersham’s and, following acquisition, General Electric’s stem cell-based drug screening capabilities. He was head of the Molecular and Cellular Biol-ogy research laboratory at GE’s Global Research Center from 2004-2007. In 2007 he joined Celgene to develop novel cell-based therapeutic candidates and subsequently development of external R&D collaborations and alliances. He joined Fate in July 20015 and his current role oversees all aspects of translational research and development of hematopoietic and induced pluripotent cell-based immunotherapeutics at Fate Therapeutics.




Return to the list

Abstract

Stewart E. Abbot, Ph.D. Is the product the process?Traditional cell therapy doctrine has taught that “the product is the process”. While changes in manufacturing approaches can result in altered product characteristics, it is almost inevi-table that cell therapy manufacturing systems will evolve during research, clinical study and commercial development. Determining the comparability of products produced before and after any manufacturing change is critical to being able to effectively implement the change. The benefits and challenges of defining target product profiles, adaptive manufacturing pro-cesses, genetic engineering, critical to qualify attributes, use of Quality by Design approach-es and process analytics in defining the comparability of human induced pluripotent stem cell-derived lymphocyte products will be discussed.




Return to the list

Biosketch

Francisca Agbanyo, PhD Chief of Blood, Cells, Tissues and Organs Division Organization / Company: Health CanadaAddress: 100 Eglantine Driveway, PL 0602BZIP code City, (State), Country: K1A OK9, Ottawa, Ontario, CanadaTel: +1-613-854-9376Fax: +1-613-954-4836e-mail: [email protected]

Francisca Agbanyo received her PhD in Biochemistry from the University of Windsor. She completed her first post-doctoral training at the University of Alberta, and her second post-doctoral training at the Scripps Research Institute in San Diego. She then joined the Canadian Red Cross Society as a Career Development Fellow.In 1998, she joined the Biologics and Genetic Therapies Directorate (BGTD), Health Products and Food Branch, Health Canada, as a Biologist/Evaluator. She became a Senior Biologist/Evaluator in 1999, the Head of the Tissues, Organs and Xenografts Section in 2001, and the Acting Manager of the Blood, Tissues and Organs Division from 2003 to 2004. She is currently the Chief of the Blood, Cells, Tissues, and Organs Division of the Centre for Biologics Evalua-tion in BGTD and is responsible for the evaluation of submissions for blood and cell therapy products. She is also (i) a member and co-chair of the Canadian Standards Association (CSA) Technical Committee on the Safety of Cells, Tissues and Organs for Transplantation and As-sisted Reproduction, and serves on a number of the CSA subcommittees; (ii) an associate member of the CSA Technical Committee on Blood and Blood Components; (iii) the Canadian delegate to the European Committee (Partial Agreement) on Organ Transplantation (CD-P-TO) and on Blood Transfusion (CD-P-TS), two steering committees established by the European Directorate for the Quality of Medicine (EDQM); and (iv) a member of the World Health Organi-zation’s Blood Regulators Network.




Return to the list

Biosketch

Jan-Eric W. Ahlfors CEO & Chief Scientific Officer Fortuna Fix500 Cartier Boulevard WestLavalH7V 5B7 CanadaTel: +1-450-781-2155 x2100Fax: +1-450-781-2199url: fortunafix.com

Jan-Eric Ahlfors is the CEO and Chief Scientific Officer of Fortuna Fix and is a specialist in direct cell reprogramming and robotic manufacturing of personalized cell therapies. Jan-Eric was the first to develop a method of direct reprogramming to produce human neu-ral precursor cells (drNPC) demonstrating that human somatic cells could be reprogrammed directly into multipotent stem cells without involving a stage of pluripotency. He developed the first high volume fully automated end-to-end cGMP (current Good Manufacturing Practic-es) manufacturing robotic platform for cells, capable of independently manufacturing multi-ple cell batches simultaneously without cross-contamination, allowing for personalized cell therapy. Fortuna Fix was founded in 2015 for the development and commercialization of the drNPC technology for neurodegeneration and neurotrauma. Investors in Fortuna Fix include Amgen Ventures. Jan-Eric has degrees in biotechnology, physics, biomedical engineering, and an MBA in the management of technology from the Worcester Polytechnic Institute. While at Worcester, Jan-Eric did one of his theses in tissue engineering in Dr. Vacanti’s lab at the University of Massachusetts Medical School. He has more than 50 granted and pending patents.




Return to the list

Abstract

Jan-Eric W. Ahlfors Large scale GMP manufacturing of individualized autologous directly repro-grammed human neural precursor cells for clinical applications

BACKGROUND – Direct cell reprogramming provides an attractive venue for clinical transla-tion of autologous cell therapies, such as directly reprogrammed personalized neural precur-sor cells (drNPC) for CNS indications such as Parkinson’s disease, spinal cord injury, traumatic brain injury and stroke. However, the time to manufacture these cells takes over 1 month and requires complex cell manufacturing steps that lend themselves to high operator batch-to-batch variability; thus cGMP manufacturing of an autologous cell therapy requires the devel-opment of new manufacturing methods to overcome the otherwise commercially unfeasible high costs of cGMP manufacturing and operator batch-to-batch variability.

CHALLENGES – Autologous cell manufacturing historically requires major infrastructure and a large number of operators. For long-term and complex cell manufacturing such as cell reprogramming, such costs would be cost-prohibitive. The standard technical challenges facing long-term and complex cell manufacturing of a large number of simultaneously manu-factured personalized cell batches are: elimination of cross-contamination between batches, minimizing batch-to-batch variability, preventing genetic instability or mutations, and mini-mizing the complexity and assay-to-assay variability of in-process and finished product QC on a large number of continuously manufactured batches.

APPROACH – A fully automated robotic GMP manufacturing system with on-board robotic QC capabilities and environmental systems to prevent any cross-contamination between simul-taneously manufactured batches provides a solution to the above challenges. Each robot could be capable of manufacturing up to 10,000 individual patient batches of 100 million cells per batch (per patient) annually (for a 6-week process per batch). The high level of consisten-cy and traceability of all cell manipulation steps achievable with robotics and computers, and the ability of the software to fine-tune the timing of execution of all cell manipulation steps based on rapid on-board in-process analysis and QC capabilities, minimizes batch-to-batch variability. Risks of genetic instability or mutations from long-term cell culture is minimized by limiting cell batches to no more than 10 population doublings (that allows 1 million starting cells to be expanded up to 1 billion cells for each patient).




Return to the list

Abstract

Jan-Eric W. Ahlfors (con’t) Large scale GMP manufacturing of individualized autologous directly reprogrammed human neural precursor cells for clinical applications

Contamination is prevented by isolating the robot within an ISO 2 environment and two degrees of pass-thru separation between the robot and a human operator, achieved by other robots feeding the manufacturing robot with raw materials and patient samples, as well as disposing of waste in negative pressure chambers. The use of only sterile disposable ma-terials in all cell manipulation steps, along with manipulations and robotic movements that prevent any aerosol contamination within the manufacturing robot, and further monitored by continuous viable particle monitoring, eliminates cross-contamination between simultane-ously manufactured batches. This is further enhanced with the ability to control the precise timing when a container is open to the ISO2 environment, significantly eliminating any risk of contamination between samples and containers. The ability of the robot to rapidly sterilize itself (with H2O2 vapor) upon detection of any viable particles ensures the maintenance of a sterile or highly aseptic field, with batches stored and sealed within an incubator (that can be separately sterilized) during the sterilization of the manufacturing robot. Integration of a wide array of on-board cell analysis capabilities allows the robotic system to perform finished product QC, and release the product for shipping only after all QC assays have passed. The final product is cryopreserved and stored by a separate integrated robotic unit while all QC assays are being completed by the robotic system; after QC release a full batch record is pro-vided by the robotic system software (FDA 21CFR.11 compliant) for QA review after which the cryovial(s) of cells can be shipped to the clinical site in a LN2 dry shipper.

CONCLUSIONS – The described robotic system has demonstrated contamination-free manu-facturing with minimal batch-to-batch variability. The robotic QC has also demonstrated min-imal assay-to-assay variability. The ability to manufacture multiple batches simultaneously without risk of cross-contamination overcomes current automated manufacturing limitations that allows only one batch to be manufactured at a time. Furthermore, the built-in detailed traceability (FDA 21CFR.11 compliant) of all manufacturing and QC steps for each individual batch significantly reduces the administrative complexity and regulatory burden of complex cell manufacturing, opening the field of autologous cell therapies to more rapid clinical trans-lation and commercialization.




Return to the list

Biosketch

Behnam Ahmadian Baghbaderani Head of Cell and Gene Therapy Development Emerging Technologies / LonzaLonza Walkersville, Inc.8830 Biggs Ford RoadWalkersville, MD 21793-0127Tel. : +1 301 378 1147Cell: +1 301 676 7061Fax : +1 301 845 0165e-mail: [email protected]

Dr. Baghbaderani is the head of Cell and Gene Therapy Development, Emerging Technologies at Lonza. He has over 14 years of experience in stem cells engineering and bioprocessing. Dr. Baghbaderani holds a PhD degree in Biomedical Engineering from the University of Cal-gary (Calgary, Canada), where he developed bioreactor protocols for large-scale expansion of human neural stem cells for clinical applications. He completed nearly three years post-doctoral program including a two-year postdoctoral fellowship at the National Institutes of Health (NIH) / National Institute of Neurological Disorders and Stroke (NINDS). His postdoc-toral research at the NIH focused on generation of human induced pluripotent stem cells, bioprocessing of both human embryonic stem cells and hiPSCs and controlled differentiation into neuronal lineage. Since joining Lonza in 2011, he has been working on developing new technologies and manufacturing processes around human pluripotent stem cells. As the head of CT Development, Dr. Baghbaderani is currently leading the process development and bioassay services, focusing on the development of cGMP compliant processes and cell char-acterization assays for different cell and gene therapy applications.




Return to the list

Abstract

Behnam Ahmadian Baghbaderani Directed differentiation of cGMP compliant human induced pluripotent stem cells into clinically relevant specialized cells from three germ-layers

Behnam Ahmadian Baghbaderani1, Mehdi Shafa1, Fan Yang1, Thomas Fellner1, Mahendra S. Rao2,3 †,

BACKGROUND: Derivation of human induced pluripotent stem cells (iPSCs) through repro-gramming has offered tremendous potential for generation of functional cell types that may be used in cell replacement therapies. In order to demonstrate the clinical relevance of iP-SCs, it is necessary to generate high quality specialized cells through controlled induction and directed differentiation processes.

CHALLENGES: Several advances have been made in the development of specialized cells from human iPSCs. However, one of the major challenges in enabling the clinical utility of iP-SC based therapies is development of robust and reproducible directed differentiated proce-dures starting from high quality iPSCs manufactured using a cGMP compliant process. In par-ticular, development of a standard cell culture system and manufacturing process that can support generation and expansion of fully characterized, high quality starting iPSCs followed by successful controlled differentiation into the cells from all three embryonic germ-layers remains a major challenge.

APPROACH: In the past, we have reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMP). Here, we exhibit that the iPSCs generated using this cGMP compliant process can differentiate into specialized cells with phenotype and cellular characteristics of neural stem cells, definitive endoderm, and cardi-omyocytes. Most importantly, we demonstrate how the use of high quality iPSCs developed under standard, cGMP compliant process and cell culture system can support unbiased dif-ferentiation and minimize variability in the controlled differentiation processes.

CONCLUSION: In conclusion, this is a viable proof-of-concept strategy for controlled induction and differentiation of the same cGMP compliant iPSC lines into the specialized cells from three embryonic lineages and a major step forward towards standardization of protocols for generation of clinically relevant cell therapy products.

Key words:cGMP, induced pluripotent stem cells, differentiation, standardization, cell therapy

1. Lonza Walkersville, Inc., Walkersville, MD, USA2. NxCell Inc, Novato, CA, USA3. NeuroQ therapeutics, Salt Lake City, UT, USA




Return to the list

Biosketch

Shirley Bartido PhD, MBA

Dr. Bartido completed her doctoral studies at New York University working on an alternative Class II processing and presentation pathway of a viral antigen. She holds a PhD in Immunol-ogy and an MBA in Pharmaceutical Management. Her postdoctoral work at Memorial Sloan Kettering Cancer Center involved the development of DNA vaccines using the melanocytic antigen tyrosinase for the treatment of melanoma. Following her postdoctoral work, she joined the Carl Icahn Institute of Gene Therapy and Molecular Medicine as an Assistant Pro-fessor to serve as the Assistant Director of the Gene Therapy Immunology Core Laboratory. In this role, she developed several immunomonitoring tools for assaying efficacy of adenoviral directed immunotherapies targeting metastatic liver cancer. This was followed by an 11-year role as the Senior Quality Manager of the MSKCC Cell Therapy and Cell Engineering Facility. In this role, she developed the QA program for the development and GMP manufacturing of autologous CD19 Chimeric Antigen Receptor T cell therapies targeting several indications in leukemia and prostate cancer as well as gene therapy for the treatment of B-Thalassemia using lentiviral transduced CD34+ HPSCs. She was integral to the design and construction of a state of the art GMP facility at MSKCC. Presently, she is the Director of Regulatory Affairs at Cellectis Inc. The company is presently involved in the development of allogeneic CAR T cells as a universal off the shelf immunotherapy for leukemias.




Return to the list

Abstract

Shirley Bartido Characterization of CAR T cells - autologous vs allogeneic sourcedPhD, MBAThe clinical success of genetically modified patient-derived T cells utilizing chimeric an¬tigen receptors has been seen in the treatment especially of B cell he¬matological malignancies in several clinical trials to date. To create universal chimeric antigen receptor (CAR) T-cell therapies—and a range of other autologous and allogeneic T-cell and natural killer cell treat-ments for patients with cancer gene-editing technologies, gene editing tools such as CRISPR/Cas9 or transcription activator-like effector nucleases (TALEN), are being utilized to target currently endogenous TCR, β-2 microglobulin (B2M) and PD1 simultaneously, so as to gen-erate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1. The next frontier will involve combining CAR transduction and gene editing so the construct positioning itself disrupts the TCR-encoding locus Like all gene-therapy approaches, a safety evaluation of the genetically modified cell pheno-type is critical. Thus, whether one uses genome editing or lentiviral delivery or some other form of gene therapy to generate a modified cell, the safety phenotype of the cell or cell pop-ulation must be assessed, irrespective of how it was generated. The regulatory requirements for CAR-T cell therapy is a challenging task because of the unique and novel nature of each therapy. Therefore, the regulatory approach taken for these cell therapies is dictated not only by the manufacture of the products but also by their intended clinical use and method of clinical delivery.




Return to the list

Biosketch

Kapil Bharti Earl Stadtman InvestigatorNEI/NIH10 Center Drive, Bldg 10, Rm 10B10Bethesda, Maryland 20892U.S.A.Tel: + 3014519372e-mail: [email protected]

Dr. Kapil Bharti holds a bachelor’s degree in Biophysics from the Panjab University, Chandi-garh, India, a master’s degree in biotechnology from the M.S. Rao University, Baroda, India, and a diploma in molecular cell biology from Johann Wolfgang Goethe University, Frankfurt, Germany. He obtained his Ph.D. from the same institution, graduating summa cum laude. His Ph.D. work involved research in the areas of heat stress, chaperones, and epigenetics. He did his postdoc at the National Institutes of Health, where he published numerous papers in the areas of transcription regulation, pigment cell biology, and developmental biology of the eye. He has won several awards, including, most recently, being selected as an Earl Stadtman Tenure-Track Investigator at NIH. His lab was recently awarded two prestigious grants: 1) the only Intramural Common Fund grant to develop a phase I Investigational New Drug (IND) for Autologous induced pluripotent stem cell derived retinal pigment epithelium tissue; and 2) a DoD grant to develop a 3D-retina tissue to model retinal diseases in vitro. His current work as the head of the Unit on Ocular and Stem Cell Translational Research involves understanding mechanism of retinal degenerative diseases using induced pluripotent stem cell technology, and developing cell-based and drug-based therapies for such diseases.




Return to the list

Abstract

Kapil Bharti IND-enabling In vitro and In vivo functional authentification of AMD-patient ...derived clinical-grade iPSC-RPE tissue

Background Age-related macular degeneration (AMD) affects more than 30 million indi-viduals worldwide. Literature evidence suggests that in the advanced AMD stage called Geographic Atrophy (GA) RPE cell death precedes photoreceptor death that leads to vision loss. Therefore, RPE replacement has been suggested as an option to treat GA. Here we develop an autologous replacement therapy for AMD using an RPE-tissue developed from patient-specific induced pluripotent stem cells (iPSCs).

Methods Clinical-grade iPSC-RPE tissues were manufactured from eight independent iPSC clones derived from three AMD patients. In vitro purity, epithelial character, and functionality of all eight iPSC-RPE tissues was authenticated using flow cytometry, tissue transepithelial resistance (TER), ability to phagocytose photoreceptor outer segments, polarized secretion of VEGF cytokine, ultrastructural and gene expression analysis. In vivo safety and functionality of iPSC-RPE from all three AMD patients was confirmed using immunocompromised rats and a swine model of RPE injury that mimics RPE loss seen in GA patients.

Results Clinicial-grade iPSC-RPE tissue from all three AMD patients have pure RPE cells (without any iPSC contamination) and have ultra-structural features of epithelial cells. RPE tis-sues derived from all eight iPSC clones show comparable TER, levels of VEGF on apical/basal sides, ability of phagocytose photoreceptor outer segments, and RPE-specific gene expres-sion that suggests adult-RPE properties. All functional features of clinical-grade iPSC-RPE are also comparable to native mammalian RPE. Clinical-grade RPE tissue is able to survive and integrate both in the rat and in the swine model of RPE injury, and is able to protect overlying photoreceptors from dying as confirmed by imaging and electrophysiological analysis of the retina.

Conclusions AMD patient’s iPSCs produce functionally authentic and mature RPE tissue in clinically compatible conditions. AMD patient derived clinicial-grade RPE tissue is safe and efficacious in rat and pig preclinical animal models. This work supports a phase I IND applica-tion to test this potential autologous cell therapy in AMD patients.




Return to the list

Biosketch

Carl Burke, Ph.D. Pharmaceutical Development & Manufacturing Sciences Janssen Research & DevelopmentP.O. Box 776Welsh and McKean RoadsSpring House, PA 19477 USAMobile: +1.267.222.2653e-mail: [email protected]

Carl is currently involved in progressing novel platforms and technologies as part of Pharma-ceutical Development and Manufacturing Sciences at Janssen Research and Development. He previously led Process and Analytical Development at Janssen Vaccines and earlier was responsible for drug product development for biologics and parenterals when he joined Janssen. Carl previously worked in drug product development at Merck developing live viral, bacterial, DNA and polysaccharide-based vaccines as well as protein and RNA therapeutics. He has contributed to the licensure of many products and has been involved in all phases of development efforts as well as transfer and support of manufacturing processes.




Return to the list

Abstract

Carl Burke, Ph.D.

Development of manufacturing processes for cell therapy presents many challenges as the field and platforms evolve. These challenges exist due to the complexities and limitations associated with the process.Raw materials can present challenges caused by limited sourcing availability and proprietary knowledge of their components and manufacturing process. In these cases, strategic collab-orations may be needed with suppliers to ensure suitable process monitoring and control, especially if critical raw materials are involved.The move toward more closed systems and automation in addition to raw material consider-ations can add significantly to the cost of goods, so appropriate development strategies are needed depending on the cell type and process.The nature of cell preparations makes particle detection difficult, so a particle control and monitoring strategy will need to be designed for different types of products with considera-tion of the process steps, raw materials and single-use components.




Return to the list

Biosketch

Björn Carlsson Group Manager, clinical assessment 3 Swedish Medical Products AgencyDag Hammarskjöldsväg 42751 03, Uppsala, SwedenTel: + 46 18 17 49 54e-mail: [email protected]

Bjorn Carlsson is an associate professor in clinical immunology at Uppsala University. Since 2008 he works as a non-clinical assessor at the Swedish Medical Products Agency. At the same time he has been appointed as the Swedish alternate in the committee of advanced therapies (CAT) at the European Medicine Agency (EMA) since 2011.




Return to the list

Abstract

Björn Carlsson Swedish Medical Products Agency, Uppsala, Sweden

When addressing the risk for tumorigenicity induced by traditional drugs/chemicals studies often involves life-long exposure of rodents (rat/mice) preformed during the later stages of drug development. When addressing the same risk for cell-based medicinal products sever-al shortcomings in terms of methods and studies make the risk-assessment cumbersome. Many issues regarding the relevance of using of human cells in an xenogenic host, batch-var-iabilities in autologous products in relation to the products tested for tumorigenicity, reso-lution and relevance of in vitro assays and statistics as to sample size normally arise during agency assessment of the risk for tumor formation following the use of a cell-based medici-nal product. Also, the timing of the tumorgenicity studies in relation to the clinical studies are often discussed as is the inclusion of children and the life-long risk for tumor-formation once exposed during the early stages of life, especially in non-lethal indications.




Return to the list

Biosketch

Joy Cavagnaro, PhD President Access BIOPO Box 240Boyce, VA 22620USATel: +548-837-9002Tel: +703-727-5241(mobile)e-mail: [email protected]

Joy Cavagnaro, PhD, DABT, Fellow ATS, RAC, RAPS Fellow consults on preclinical devel-opment and regulatory strategies for drug, biologics and device combinations. Her career spans academia, the CRO and biotechnology industries and government. During her tenure at CBER/FDA she was appointed to the SBRS and served as FDA’s safety topic lead and rappor-teur for “ICH S6.” She was the first to advocate the “case-by-case” science based approach for preclinical safety evaluation, which is consistent with traditional principles but embraces new practices, is questions-based, data driven and targeted based on product attributes to obtain maximum information with judicious animal use. Prior to joining FDA, Dr. Cavagnaro was principal study director for biotechnology products at Covance. She is Past Chair of RAPS and the National Capital Area Chapter of SOT. In 2011 she received SOT’s Biotechnology Spe-cialty Section first Career Achievement Award. She is Founder, Past Chair and current ex offi-cio member of the leadership committee of BioSafe, an expert preclinical science committee within BIO. She is past North American Chair of DIA’s Biotech Community, past Chair of the Clinical and Regulatory Affairs Committee and Translational Science & Product Development Committee of the ASGCT. She was a member of the Scientific Advisory Committee on Alter-native Toxicological Methods and is currently an advisor and member of the Grants Working Group of the California Institute of Regenerative Medicine. Dr. Cavagnaro is currently a Chair of Advarra, an independent IRB. She serves on multiple SAB’s and consults and lectures inter-nationally on translation and risk assessment of novel therapies. She has co-authored numer-ous white papers and chapters related to various aspects of preclinical safety assessment.The book she edited “Preclinical Safety Evaluation of Biopharmaceuticals A Science-BasedApproach to Facilitating Clinical Trials” published by John Wiley & Sons, NJ, 2008 is commonlyreferred to as the “BioBible”.




Return to the list

Biosketch

Abla A Creasey, Ph.D. Vice President, Therapeutics & Strategic Infrastructure California Institute For Regenerative Medicine1999 Harrison Street, Suite 1650Oakland, California 94618Tel.: 510 679 [email protected]

Abla Creasey is the Vice President of Therapeutics and Strategic Infrastructure. As a previ-ous Associate Director of Therapeutics and most recently, as Sr. Director of Strategic Clinical and Regulatory Infrastructure, Abla has been instrumental in building up CIRM’s clinical port-folio and in working closely with our grantees who attained three of the first 11 RMAT-expe-dited pathway designations from the FDA. She has worked with the Accelerating Center to launch novel accelerating resources for product development, regulatory strategy and phar-maco-economics. In her current role, Abla will ensure that the therapeutics team will contin-ue to meet their big six strategic goals with integration of critical resources from the Clinical Advisory Panel program, Alpha Clinics and the Accelerating Center.Abla has broad and extensive experience in science, technology, and pharmaceutical product development. Prior to joining CIRM in 2016, she was at Johnson & Johnson for 12 years. While at Johnson and Johnson, Abla was a Senior Scientific Director in Pharmaceutical Develop-ment & Manufacturing Sciences at Janssen and prior to that, she was, an Executive Director, heading drug delivery, pharmacology, analytical characterization, clinical & quality at Ad-vanced Technologies & Regenerative Medicine (ATRM), another J&J company. Prior to ATRM, Abla was Vice President of Biological Sciences at ALZA Corporation, where she headed dis-covery efforts in formulation, preclinical and oral drug delivery. Before joining ALZA in 2004, Abla held senior-level positions in R&D, clinical development, and regulatory affairs within the biotechnology industry including Chiron Corporation and Cetus Corporation.Abla received a B.S. in biology from the College of Notre Dame in Belmont California, and earned her Ph.D. in medical microbiology from the University of California, Berkeley. She completed a post-doctoral fellowship at the Stanford University School of Medicine in infec-tious disease, biochemistry, and immunology.




Return to the list

Biosketch

Kathleen Francissen, PhD Senior Director, Pharma Technical Regulatory, Genentech, A Member of the Roche Group

Dr. Francissen serves as Senior Director of CMC Regulatory at Genentech and as a member of the Board of Directors of CaSSS, a non-profit organization that enables industry, academic, and regulatory professionals to work together to resolve scientific challenges in biopharma-ceutical development and regulation. She is now the CMC regulatory lead strategist for a personalized cancer vaccine program. Kathy joined Genentech in 1997 as a Scientist in Ana-lytical Chemistry where she conducted proteomics studies of host cell proteins derived from mammalian and bacterial cells. Since then, Kathy has held various roles, including Senior Scientist and then Director of Protein Analytical Chemistry. In addition to her functional lead-ership roles, she has led cross-functional teams, including the CMC development team that implemented multiple post-approval changes for one of the company’s largest Mab products. Prior to joining Genentech, Kathy conducted postdoctoral studies in proteomics at the U.S. Department of Energy and was a Visiting Scientist at the Max Planck Institute for Marine Mi-crobiology in Bremen, Germany.




Return to the list

Biosketch

Andrew Gaffney, PhD Product Manager, PluripotentSTEMCELL Technologies1618 Station Street, Vancouver, BC, Canada, V6A 1B6Tel: +1 604-668-1670Fax: +1 604-877-0704e-mail: [email protected]

Andrew Gaffney completed his PhD in Pediatric Oncology from the University of Leeds, UK, where he successfully established a human embryonic stem cell disease model of Ewing sarcoma. He joined STEMCELL Technologies in 2014 as a Global Technical Specialist where he provided advanced customer support in the areas of human pluripotent stem cell (hPSC) maintenance and differentiation. Since 2016, Andrew has been working as the Product Man-ager for STEMCELL’s PSC portfolio of products. He works closely with renowned stem cell scientists in both industry and academia to monitor the requirements needed for establish-ing successful hPSC-based disease models, drug screens and cell therapy applications.




Return to the list

Biosketch

Christopher Goldring Chair of Molecular and Cellular Pharmacology, MRC Centre for Drug Safety Science,University of Liverpool,U.K.

CG has more than twenty years of experience of molecular bioanalysis, working with cell culture and in vivo models. He leads the molecular and cellular toxicology group within the MRC Centre for Drug Safety Science (CDSS), a leading UK centre based at the University of Liverpool, with a critical mass of scientists studying mechanisms of adverse reactions to therapeutics, and which was the coordinator of the Mechanism-based Improved Prediction of Drug-Induced Liver Injury (MIP-DILI) IMI programme. He plays a leading role in the new IMI project TransQST, which will develop quantitative systems toxicology models to improve our understanding of adverse drug reactions. He recently led the liver project in the UK Regen-erative Medicine Safety platform, developing innovative methods for the assessment of the safety of stem cells and regenerative therapies, including cell labelling using nanoparticles and cell tracking.




Return to the list

Abstract

Christopher Goldring Imaging technology and biodistribution studies

UKRMP Safety and Efficacy Hub and MRC Centre for Drug Safety Science, University of Liverpool, U.K.

Regenerative medicine therapies (RMTs) hold enormous potential for a variety of currently incurable conditions with high unmet clinical need. At the same time, we require a clear understanding of the potential hazards (and associated risks) of RMTs so that these new medicines can be accelerated into the clinic with full confidence. Therefore, in the Safety and Efficacy Hub of the UK-based Regenerative Medicine Platform, we have established a pre-clinical toolkit of novel nanoprobes and reporters for cell tracking which gives us the capacity to label different cell types. With flexibility of both chemistry and multimodal imag-ing aligned with mechanistic biomarkers which can be used in assessment of clinical benefit, this provides a combination that begins to address the key issues that determine the safe and efficacious use of RMTs in man. In tandem with the Hub’s interdisciplinary operation, we have employed these resources to work towards our objectives of evaluating safety and efficacy of transplanted cells in relevant pre-clinical models. This talk will focus on some key areas of progress in the field of imaging and biodistribution, discuss ongoing gaps in the field, and give examples of imaging strategies to assess tumorigenicity pre-clinically.




Return to the list

Biosketch Return to the list

Thorsten Gorba Translating Center DirectorIQVIA Stem Cell Center10188 Telesis CourtSuite 400San Diego, CA 92121, USATel: +1 858 646 2134Fax: +1 858 435 1123e-mail: [email protected]

As Translating Center Director of the CIRM infrastructure funding program supported IQVIA Stem Cell Center Dr. Gorba is the principal source of and go-to person for stem cell exper-tise at IQVIA, and is responsible for business development and sustainable operations of the Stem Cell Center; additionally he serves as CMC Strategy Lead for Cell and Gene Therapeu-tics. Dr. Gorba brings to this role extensive experience in Stem Cell Research and Clinical Stage Translation, working in and with leading academic groups and Industry, and in alliance partnerships, including European Framework, large-scale Research Consortia. As sponsor employee in the industry he contributed to cell therapy clinical trial studies in Parkinson’s disease, spinal cord injury and age-related macular degeneration.Previously he has held management level positions in the Regenerative Medicine biotechnol-ogy sector at Living Cell Technologies Ltd., Stem Cell Sciences Ltd. and StemCells Inc., in-volved in all aspects of the regenerative medicine field; translational and preclinical research, stem cell-based screening of small molecules and protein factors, CMC assay and process development, culture automation, GMP manufacturing and regulatory filings. Successful stem cell assay/screening projects for Pharmaceutical industry clients included Sanofi and Pfizer. Dr. Gorba earned his Ph.D. in Developmental Neuroscience from Ruhr-University Bochum, Germany and received his postdoctoral education in Stem Cell Biology under Prof. Austin Smith at the University of Edinburgh, UK.




Biosketch

Elwyn Griffiths Consultant in Vaccines and Biotherapeutics3 The FarthingsKingston upon ThamesSurrey , KT” 7PT , UKTel: + 44 208 549 1255e-mail: [email protected]

Dr Elwyn Griffiths retired as Director General, Biologics and Genetic Therapies Directorate, Health Canada, at the end of October 2011 and now lives in the UK. He joined Health Can-ada in 2003 on his retirement from the WHO. Dr Griffiths has a PhD and a DSc degree from the University of Wales. Following postdoctoral positions at the National Research Council and McMaster University, Canada, he joined the staff of the MRC National Institute for Med-ical Research, London, UK, where he worked for over ten years. In 1980 he became a senior member of staff at the National Institute for Biological Standards and Control, UK, and in 1994 was appointed Chief, Biologicals, and later Coordinator, Quality Assurance and Safety of Biologicals, at the WHO. Here he was responsible for WHO`s program for providing inter-national written and physical standards for vaccines, blood products and biotherapeutics, including biotechnology derived and gene therapy products. Dr Griffiths has published widely in the field of microbial pathogenicity, vaccines and the standardization and control of bio-logicals and provided scientific and regulatory advice over many years to the Canadian, UK, European and other regulatory agencies, as well as to the WHO. He has been a member of the WHO Expert Committee on Biological Standardization since 2007 (Chair 2010-2015) and since returning to the UK, a consultant in vaccines and biotherapeutics and a member of the Clinical Trials, Biologicals and Vaccines Expert Advisory Group of the UK Commission on Human Medicines (2012-2017). He is a member of the Board of the International Alliance for Biological Standardization (IABS) and recently became consultant to the Secretariat of the Coalition on Epidemic Preparedness Innovations (CEPI).




Return to the list

Abstract

Elwyn Griffiths Historical perspective: the importance of early regulatory guidance for biothe-rapeutics

Just over thirty years ago, novel rDNA derived medicinal products appeared on the horizon and revolutionized the field of human biotherapeutics, in vitro diagnostics and vaccines. As with many other novel technologies, a new set of issues for consideration by both industry and regulators were generated by these biotechnologies. Potential concerns arose from the novel processes used in manufacture, from product and process related impurities, and from the complex structural and biological properties of the products themselves. Factors that received particular attention included possible variant sequences in the DNA used in pro-duction, contamination by possibly oncogenic host cell DNA in products derived from trans-formed mammalian cells and the presence of adventitious viruses. There was also the risk that recombinant biotherapeutic proteins might be immunogenic. Recognizing the intricacies of the manufacturing processes for recombinant proteins, regulatory measures were rapidly put in place and guidelines on their development, production and quality control issued by the EMA, FDA and WHO. Such guidelines, subsequently updated, provided a framework for moving forward with novel biotechnologies and rDNA derived products became the best characterized of all biologics, as well as safe and effective medicines which play a major role in today’s medical practice. The presentation will discuss some of the issues of rDNA bio-technology, the progress made in addressing them and the impact on subsequent regulatory guidance, especially the importance of international consensus. Like the novel rDNA prod-ucts of thirty years ago, cell therapies are the present emerging area of biomedical research and development and would benefit from a set of common principles that may facilitate a convergence of regulatory approaches.




Return to the list

Biosketch

Tadaaki Hanatani, PhD Associate Professor Kyoto University53 Kawahara-cho, Shogoin, Sakyo-ku606-8507, Kyoto, JapanTel: +81-75-366-7008Fax: +81-75-366-7180e-mail: [email protected]

Tadaaki Hanatani is Associate Professor of Center for iPS Cell Research and Application (CiRA) at Kyoto University with responsibility for regulatory matters. He has worked at Min-istry of Health, Labour and Welfare of Japan since 2002, and is seconded from the Minitsry to CiRA.He recieved his Master’s degree from Osaka University and Ph.D. from Nagoya city University.




Return to the list

Biosketch

Takao Hayakawa, PhD Guest Professor of Kindai University & Osaka University Emeritus Investigator of the NIHS of JapanIABS Board MemberChair, Cell & Gene Therapy Committee

Dr Takao Hayakawa is the Senior Advisor & Guest Professor of the Pharmaceutical Re-search and Technology Institute, Kindai University, Guest Professor of Graduate School of Medicine, Osaka University, the former Director General & President of the Chemo-Sero-Ther-apeutic Research Institute and an Emeritus Investigator of the National Institute of Health Sciences of Japan. He was involved in numerous scientific committees of various Ministries of Japan and served as the chairmen of a number of committees, such as the Committee on the Japanese Pharmacopoeia; the Committee on Biotechnology Products of the Ministry of Health, Labour and Welfare; the Committee on Reviewing and Promoting National Research Projects on Medical/Pharmaceutical Sciences sponsored by Japanese Government, as well as the Planning Expert Committee of the Food Safety Commission of Cabinet office. He is the author or coauthor of over 600 publications in biochemistry, biotechnology, cell biology and the pharmaceutical sciences.Internationally, Dr Hayakawa has played an active role as a member of the ICH Expert Work-ing Groups on biotechnological/biological products (Q5B, Q5C, Q5D and Q6B), CTD and phar-macopoeial interchangeability (Q4B). Among his other responsibilities Dr. Hayakawa is rap-porteur for Q5A and Q5E, a member of Pharmacopoeia Discussion Group (USP/EP/JP), and a temporal adviser of WHO. In Spring of 2012, a royal decoration was conferred on Dr. Hayakawa by Japanese Emperor. He received the Order of the Sacred Treasure, Gold Rays with Neck Ribbon. He also received various awards. These include : ‘2014 Prize for Science and Technology (Research Category) ‘ by the Minister of Education, Culture, Sports, Science and Technology, for development of in-novative new gene transfer methods into mammalian cells ; ‘ 4th William S. Hancock Award’ for outstanding achievements in CMC regulatory science ; and ‘ The JSRM Achievement Award 2015’ from Japanese Society of Regenerative Medicine (JSRM), for his outstanding achievements in and contributions to regenerative medicine field over a long time.




Return to the list

Biosketch

Tatsuo Heki Senior Expert Fujifilm Corporation9-7-3Akasaka, Minato-ku, Tokyo107-0052. JapanTel: +81-3-6271-2650Fax: +82-3-6271-3191e-mail: [email protected]

Tatsuo Heki is Senior Expert at Fujifilm Regenerative Medicine Business Division. He is currently the chair of Japanese Mirror Committee for ISO/TC276 (Biotechnology). He is also leading the ISO/TC276/WG4 (Bioprocessing) at international level, which is working on the standardization in the field of regenerative medicine. He represents the Standardization Com-mittee at FIRM (Forum for Innovative Regenerative Medicine), which is the primary industry organization promoting regenerative medicine in Japan. He has been working on standards since the days of Advanced Photographic System, which is the last photographic film system in its history. He received M.S. degree in synthetic chemistry from The University of Tokyo.




Return to the list

Biosketch

Karin Hoogendoorn

Karin has 20 years of experience in the pharmaceutical industry, predominantly in the field of mAbs, (viral based) vaccines, and cell and gene therapy products. Currently, she holds a position as scientist ATMP product development at the Leiden university medical centre, The Netherlands. She holds MSc degrees in Biology and Bio-Pharmaceutical Sciences from Leiden University and a PharmD degree from Utrecht University, The Netherlands.




Return to the list

Biosketch

Shawna M. Jackman, Ph.D., DABT Principal Research Scientist Charles River Laboratories Photobiology and Cellular Therapeutic Safety905 Sheehy DriveHorsham, Pennsylvania 19044U.S.A.Tel.: +1 267 532 3824Fax.: +1 215 443 8587E-mail: [email protected]

Dr. Jackman is a Principal Research Scientist in the Photobiology and Cellular Therapeutic Safety group, with 15 years of in vitro and in vivo experience in preclinical safety evaluation, including 13 years at Charles River Laboratories, Pennsylvania designing and conducting specialty preclinical toxicology assessments. With doctoral experience in cell and molecular biology, she provides program management and scientific guidance to cell and gene therapy developers for preclinical program designs to meet regulatory expectations. As a GLP Study Director, she is responsible for the oversight and conduct of safety studies for cell/gene ther-apies including assessment in specialty models of disease and immunocompromised rodent strains.




Return to the list

Abstract

Shawna M. Jackman, Ph.D., DABT Study design considerations for in vivo tumorigenicity assaysThe potential risk of tumorigenicity remains an important concern in the development of stem cell therapy products. Tumorigenicity evaluations of cell-based therapies present unique challenges in nonclinical study designs and execution due to various cell derivations, manufacturing processes/ex vivo manipulations employed for these products and translata-bility of animal models. Nonclinical in vivo investigations must be specifically designed with consideration of the specific cell product attributes and indication to provide the developer valuable information to assess the safety for humans use and to meet regulatory expecta-tions. In this presentation, considerations for the design of in vivo tumorigenicity studies will be discussed including test system selection, route of administration, impact of cell persis-tence and study duration.




Return to the list

Biosketch

Shin Kawamata, MD, PhD Director, Research and Development Center for Cell Therapy Foundation for Biomedical Research and Innovation (FBRI) TRI#3061-5-4 Minatojimaminamimachi, Chuo-kuKobe 650-0047 JAPANTel: +81-78-306-0681Fax: +81-78-306-2036e-mail:[email protected]

Shin Kawamata studied physics at Faculty of Science of Kyoto University, Japan (1975-1981) and medicine at medical school of Kobe University, Japan (1984-1990). He started his carrier as a medical doctor (hematology) and got PhD degree from Kyoto University (1998). He de-veloped various human leukemia models in SCID mice in his post doctoral period at Systemix Co., Palo Alto USA and Stanford University (1998-2001). Shin became the group leader of Regenerative Medicine Research Unit and the general manager of Cell Processing Facility in Foundation for Biomedical Research and Innovation (FBRI) (2002-2014) and the Director of Research and Development Center for Cell Therapy (2015). His major research field is stem cell biology and hematopoietic cell differentiation.




Return to the list

Abstract

Shin Kawamata, MD, PhD Design of in vivo tumorigenicity assays for iPSC-derived cell product - Lesson from clinical studies in Kobe -

Background and challengeThere is no obvious consensus for the set of QC tests for release and tumorigenicity assay to address the safety of the PSC-derived cell product. We discuss and propose it in this session.

Proposed approach and conclusionWe propose safety tests for PSC-derived product. It consists of in vivo tumorigenicity assay via clinical route and subcutaneous transplantation assay for characteristic analysis, and gene expression profiles for the pre-determined set of molecules by qRT-PCR, visual inspec-tion during process and sterile tests for release. For characteristic tests for the product, a risk assessment based in vivo tumorigenicity test is indispensable to evaluate tumorigenic potential.βTherefore, a series of pilot studies shall be conducted prior to the assay to extract potential risks and defined the design of the assay. In addition to tumorigenicity assay via clinical route, subcutaneous transplantation assay shall be conducted in parallel as a long term QC test of final products, if applicable. We regard this subcutaneous assay as a long term “in vitro” tumorigenic assay by using a mouse as incuba-tor. It gives histological analysis of transplants in term of proliferation potential and purity of target cell product in the transplant in long term culture. Gene expression prolife of molecules that define the characteristic of product by qRT-PCR and visual inspection of final product during process provide QC information for release. In this context, In vitro tumorigenicity assay may not be necessary if subcutaneous transplanta-tion assay is conducted. WGS gives useful information for genetic stability as a basic science, but will not for making go/no go decision in clinic that always accompanies risk. Therefore, the tests or assays that will not give a go/no go decision can be skipped.




Return to the list

Abstract

Hironobu Kimura

The issue in allogeneic transplantation is immune rejection caused by the recipient’s im-mune system. The allogeneic graft rejection is assumed to be mainly caused by recipient T lymphocytes, which recognize human leukocyte antigen (HLA) expressed on cell surface to distinguish between donor and recipient cells. Universal donor cell approach, which is remov-ing HLA molecules from cell surface, might be one solution to overcome this issue. Universal donor induced pluripotent stem cell (iPSC) might be useful for starting materials of any trans-plantable cell type and to any patientWe collaborate with Universal Cell Inc. to establish the universal donor iPSC line from our cGMP grade iPSC seed bank. Using Universal Cell’s gene editing technology, we removed HLA-molecules from the cell surface by disrupting B2M gene for HLA class I molecules and RFXANK gene for HLA class II molecules. To avoid NK cell’s missing-self response, we engi-neered the cell to express only HLA-E molecules, which is non-polymorphic HLA class I mole-cule and expressing on the surface of most cell types. Here, I would like to introduce recently established our universal donor iPSC line.




Return to the list

Biosketch

Agnete Kirkeby Associate ProfessorDanish Stem Cell Center (DanStem), University of CopenhagenBlegdamsvej 3BCopenhagen 2200DenmarkTel: +45 51685353e-mail: [email protected]

Agnete Kirkeby performed part of her graduate research project with the field pioneer Lorenz Studer at the Sloan Kettering Institute (New York), and in 2009 she went on to perform her postdoc in the group of Malin Parmar at Lund University (Sweden). She has over the years built up a unique expertise in using human pluripotent stem cells for production of sub-type-specific neural cells, and has developed protocols for accurate patterning of neural cells towards different regional fates (Kirkeby et al., Cell Reports 2012). This work has led to the development of a promising stem cell treatment for Parkinson’s Disease (PD) (Grealish et al., Cell Stem Cell 2014, Grealish et al. Stem Cell Reports 2015), which is currently in trans-lation to the clinic in collaboration with Prof. Malin Parmar and Prof. Roger Barker (Kirkeby et al., Cell Stem Cell 2017, Nolbrant et al., Nature Protocols 2017, Kirkeby et al., Prog. Brain Research 2017), and Agnete is playing a key role in coordinating the GMP manufacturing these cells for clinical trial. In recent years, Agnete has also built up her own line of research by initiating a cross-disciplinary collaboration combining stem cell patterning protocols with microfluidic techniques to produce an in vitro model of the human developing brain. Based on a junior group leader start-up package from the Danish Stem Cell Center (DanStem), she moved her group to the University of Copenhagen in the beginning of 2017.




Return to the list

Abstract

Agnete Kirkeby Developing predictive assays to assess function and purity of dopaminergic progenitors for treatment of Parkinson’s DiseaseBackground: Stem cell treatments for Parkinson’s Disease (PD) are expected to reach clin-ical trials soon. The most successful approaches for cell replacement therapy in PD involve transplantation of immature dopaminergic progenitors derived from human pluripotent stem cells (hPSCs), which subsequently undergo phenotypic and functional maturation in vivo. De-veloping assays which can reliably predict the long-term graft outcome already at the early progenitor stage is therefore a major challenge in the clinical translation of cell products for PD. Materials and Methods: We have taken an unbiased approach to retrospectively identify predictive markers expressed in dopamine neuron progenitors that correlate with graft out-come in an animal model of PD. This was done by RNA sequencing of >30 batches of grafted human embryonic stem cell (hESC)-derived dopaminergic progenitors, and subsequently correlating the RNA expression results to the in vivo outcome of the grafted cells (assessed by graft size and dopaminergic neuron yield).Results: We found that many of the commonly used dopaminergic progenitor markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we have developed a good manufac-turing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs, and we have composed a QC panel based on flow cytometry and qRT-PCR to reliably predict the purity and in vivo performance of new batches of cells.Conclusions: When dealing with transplantation of immature progenitor cells, we conclude that it is necessary exert major caution in drawing conclusions on cell product functionality based purely on in vitro criteria, if these criteria have not been proven to accurately predict in vivo function. We recommend that exhaustive and persistent in vivo tests of many cell batches is performed prior to GMP production in order to properly understand the relation-ship between the cell phenotype in vitro and the cellular maturation and function in vivo.

References: 1. Nolbrant S, Heuer A, Parmar M, and Kirkeby A. Generation of high-purity ventral midbrain dopaminergic progenitor cul-tures for in vitro maturation and intracerebral transplantation. Nature Protocols, 2017 Sep; 12(9): 1962-792. Kirkeby A, Nolbrant S, Tiklova K, Heuer A, Kee N, Cardoso T, Ottosson DR, Lelos MJ, Rifes P, Dunnett SB, Grealish S, Perlmann T and Parmar M. Predictive markers guide differentiation to improve graft outcome in clinical translation of hESC-based cell therapy for Parkinson’s Disease. Cell Stem Cell, 2017 Jan; 20(1): 135-148.3. Lehnen D, Barral S, Cardoso T, Grealish S, Heuer A, Smiyakin A, Kirkeby A, Kollet J, Cremer H, Parmar M, Bosio A and Knöbel S. IAP-Based Cell Sorting Results in Homogeneous Transplantable Dopaminergic Precursor Cells Derived from Human Pluripotent Stem Cells, Stem Cell Reports, 2017 Sep; doi: 10.1016




Return to the list

Biosketch

Ivana Knezevic, MD, PhD Group Lead, Norms and Standards for Biologicals, TSN/RHT/EMP/WHO World Health OrganizationDepartment of Essential Medicines and Health Products (EMP), (office: L276)Health Systems and Innovation (HIS) ClusterAvenue Appia 201211 Geneva 27SwitzerlandTel: + 41 22 791 31 36Fax: + 41 22 791 49 71e-mail: [email protected]

Dr Knezevic is Specialist in Medical Microbiology and Parasitology. She received her MD from the University of Novi Sad, MSc in Medicine (Microbiology) and PhD in Medicine (Virology) from the University of Belgrade, Republic of Serbia. Dr Ivana Knezevic has 24 years of profes-sional experience in standardization, scientific and regulatory overview of biologicals. Dr Knezevic is a Scientist at the WHO Biological Standardization Programme, which she joined in September 2000. Since 2006, she has been leading the team for standardization of vaccines and biological therapeutics in WHO Headquarters. Main aspects of the work include development and establishment of WHO International Standards as well as the assistance to regulators, manufacturers and other users of these standards. Being responsible for 9 WHO Collaborating centers (UK, Japan, Australia, USA, Republic of Korea, Canada, China, Germany and Switzerland), Dr Knezevic initiated numerous scientific projects of importance for global public health. In 2012, she created a network of the insti-tutions that are playing a leading scientific and regulatory role in their countries. In addition, continuous collaboration with National Regulatory Authorities, manufacturers, academia and other experts in the area of biological products is one of the main aspects of her work.Dr Knezevic is the author of many publications and is also contributing to the peer-review scientific journals with the international reputation. Passionate about education, Dr Knezevic is contributing to the development of training pro-grammes as well as materials for distance learning and teaching in class in the area of vacci-nology and biologicals.




Return to the list

Abstract

Ivana Knezevic, MD, PhD WHO standards for cell therapies: key issues in defining quality, safety and effi-cacy

BACKGROUND Advances in technology and research has resulted in the development of novel cell-based investigational products that require appropriate regulatory oversight. One of the goals of cell therapy products is to provide new opportunities for treating patients suf-fering from severe diseases for which effective treatment may not exist or may require long and usually costly treatment using conventional medicines.

CHALLENGES AND OPPORTUNITIES Rapid development of cell therapies requires an ur-gent international initiative and global consensus regarding the evaluation of quality, safety and efficacy of these products. Diversity among cell therapy products due to different origin, target disease, intended use, patients and their specific needs, application sites, application procedures and cell processing methods is imposing a number of challenges to manufactur-ers, developers and regulators of these products, as well as to patients.

PROPOSED APPROACH The WHO Expert Committee on Biological Standardization (ECBS) has been reviewing progress in the development of a wide range of cell therapies as well as scientific and regulatory considerations in evaluating these products. To ensure access to cell therapies of assured quality, discussion at the global level with regulators, manufacturers and developers of cell therapy products, health care providers, public health officials, patients and other important players needs to continue and to involve all countries.

CONCLUSIONS WHO is in a unique position to provide standards for global use, but which written and measurement standards should be developed first is still an open question. It was recognized that consensus on definitions and terminology would be particularly helpful for countries that are now setting their own national requirements. A brief summary of pre-vious discussions of the ECBS regarding the standardization of cell therapies as well as key issues in defining principles for quality, safety and efficacy evaluation of cell therapy products will be included in this presentation. It is expected that early guidance will be updated as new information is obtained and experience gained.




Return to the list

Biosketch

Jane S. Lebkowski, PhD President R&D Regenerative Patch Technologies150 Gabarda WayPortola Valley, CA 94028, USATel: +1 650 799 [email protected]

Jane Lebkowski has been actively involved in the development of cell and gene therapies since 1986 and is President of R&D at Regenerative Patch Technologies (RPT), a biotech-nology firm developing composite stem cell-based implants targeting restoration of retinal architecture and function in patients with macular degeneration. In this role, Dr Lebkowski oversees all of RPT’s operations. From 2013-2017, Jane Lebkowski also served as Chief Sci-entific Officer and President of R&D at Asterias Biotherapeutics Inc, where she headed all preclinical, product, regulatory, and clinical development of Asterias’ regenerative medicine and dendritic cell based-cancer immunotherapy products. Prior to joining Asterias, Dr. Lebkowski was Senior Vice President of Regenerative Medicine and Chief Scientific Officer at Geron Corporation. Dr. Lebkowski led Geron’s human embryonic stem cell program from 1998-2012 and was responsible for all research, preclinical development, product develop-ment, manufacturing, and clinical development activities supporting cell-based therapies for several regenerative medicine indications including spinal cord injury and cardiovascular disease. From 1986-1998, Dr. Lebkowski was Vice President of Research and Development at Applied Immune Sciences where she directed activities to develop T cell-based cancer immu-notherapies for solid tumors, hematologic malignancies and AIDs. Following the acquisition of Applied Immune Sciences by Rhone Poulenc Rorer (RPR, currently Sanofi), Dr. Lebkowski remained at RPR as Vice President of Discovery Research. During Dr. Lebkowski’s tenure at RPR, she coordinated preclinical investigations of gene therapy approaches for treatment of cancer, cardiovascular disease and nervous system disorders, and directed vector formu-lations and delivery development. Dr. Lebkowski received her Ph.D. in Biochemistry from Princeton University in 1982, and completed a postdoctoral fellowship at the Department of Genetics, Stanford University in 1986. She has published over 80 peer reviewed publication and has 13 issued U.S. patents. Dr. Lebkowski has published over 80 peer reviewed publication and has 13 issued U.S. pat-ents. Dr. Lebkowski has served on the board of Directors of the American Society for Gene and Cell Therapy and on numerous scientific advisory boards and professional committees including those supported by ASGCT and ISSCR.




Return to the list

Biosketch

Benjamin Le Quéré Business Manager, Bioprocess Solutions Saint-Gobain18, avenue d’Alsace92400 Courbevoie, FranceTel: +33 1 47 62 30 00e-mail: [email protected]

Benjamin Le Quéré is the Business Manager of the Bioprocess Solutions business unit in Saint-Gobain, specifically targeted at the biopharmaceutical and cell therapy manufacturing markets. Benjamin previously served as Director of Strategy for Saint-Gobain Performance Plastics and as Business Manager for the Biotechnology and Laboratory markets. He holds a Ph. D. in Molecular Biology from the University Pierre and Marie Curie (Paris VI) and a M. B. A. from the College des Ingenieurs, Paris.




Return to the list

Abstract

Benjamin Le Quéré Enhancing economic reality for cell based medicines through manufacturing optimization

Introduction: Cell therapy showed its potential to change how diseases are treated. With the recent FDA approval of Novartis’ CAR-T therapy, Kymriah™ and Kite/Gilead’s CAR-T ther-apy, Yescarta™, the market has seen rapid growth in recent years garnered from the encour-aging efficacy of the often personalized treatment approach.Challenges: With the growing interest in bringing these products to fruition comes the in-creasing importance, and ultimate challenge, of selecting appropriate systems and materials for manufacturing to generate cost-effective products. Unlike in traditional scale-up pro-cesses, the scale-out approach required for many of these products currently results in little benefit from economies of scale.Proposed Approach: Many challenges of cell therapy manufacturing can be addressed with varying levels of connectivity and automation. Nonetheless, implementation of these ap-proaches requires thorough consideration to the impact on cost of goods (COG). Specifically, automation can lead to more complex and often custom-designed disposable systems that involve critical understanding of material selection, design, and validation. Conclusions: Sustainable commercialization of cell therapy products entails careful atten-tion and eventual optimization of COG. Designing and manufacturing hardware and subse-quent disposables for automation is an involved process that is rarely linear. Thinking about the manufacturing end game early allows for appropriate level of planning and optimization.




Return to the list

Biosketch

Stephen S. Lin, Ph.D. Senior Science Officer Organization / Company California Institute for Regenerative MedicineAddress1999 Harrison Street, Suite 1650Oakland, CA 94612USAZIP code City, (State), Country Tel: 510-340-9144Fax: 510-340-9144e-mail: [email protected]

Stephen Lin is a senior science officer at California’s stem cell agency, CIRM. He joined the Agency in 2015 to oversee the its $32M initiative to create a repository of iPSCs from over 2500 individuals covering both genetically complex and rare diseases, as well as a $40M genomics initiative that applies cutting edge genomics and bioinformatics approaches to stem cell research and therapeutic development. He is also program lead on a $15M award to create a preclinical research organization termed the Translating Center that focuses on preparing stem cell therapy candidates for clinical trials through support with process devel-opment, safety/toxicity studies, and manufacturing. From 2012 he had been a staff scientist and team lead at Thermo Fisher Scientific (formerly Life Technologies). Prior to that he was a scientist since 2006 at StemCells, Inc of California in the area of liver cell therapeutics. Dr. Lin received his Ph.D. from Washington University in St. Louis under Jeffrey Gordon and did his postdoctoral research at Harvard University under Stanley Korsmeyer.




Return to the list

Biosketch

Anthony Lubiniecki Board Member, Treasurer

Anthony S. Lubiniecki, Sc.D, retired in May, 2017 as Senior Scientific Director & Fellow, CMC Strategy, Pharmaceutical Development & Manufacturing Sciences at Janssen R&D, LLC. During his 43 years in industry, he worked on development of over 50 recombinant derived investigational products using both microbial and eukaryotic expression systems, of which thirteen have become marketed products, including Simponi, Stelara, Sylvant, Tremfya, and Darzalez during his 13 years at Janssen R&D LLC. He also served as Vice President of Bio-pharmaceutical Development for GlaxoSmithKline, SmithKlineBeecham, and Smith Kline & French for 16 years, building a 400-person organization. He also spent 6 years at Genentech directing the development of tissue plasminogen activator and other recombinant DNA prod-ucts in cell culture.Tony also has been active in shaping regulatory policy by serving as a Pharmaceutical Re-search & Manufacturers of America representative to the International Conferences on Harmonization (ICH) Expert Working Groups for 6 Q5-Q7 guidance documents, and served as Rapporteur for two of them (ICH Q5D & Q5E). He has sat on review boards and advisory committees for the Department of Health & Human Services, Center for Biologics Evaluation & Research, and the National Academy of Sciences. He earned his Doctor of Science degree in Public Health Microbiology from the University of Pittsburgh in 1972, and his Bachelor of Science degree in Biological Sciences from Carnegie Mellon University in 1968. He is also Adjunct Professor of Chemical & Biochemical Engineering at University of Maryland Baltimore County since 1991.




Return to the list

Biosketch

Steven S. Oh, PhD Deputy DirectorDivision of Cellular and Gene TherapiesCenter for Biologics Evaluation and ResearchFood and Drug Administration Silver Spring, MD 20993, U.S.A.Phone: 240-402-8337Email: [email protected]

Dr. Steven Oh provides leadership in reaching regulatory decisions on investigating and mar-keting regenerative medicine therapy including cellular and gene therapy products, tissue-en-gineered products, combination products, and point-of-care devices reviewed by CBER, FDA. Dr. Oh is actively engaged in developing CBER policies that address regulatory challenges involving cross-cutting science and emerging technologies in regenerative medicine thera-py. He is also involved in international standards activities in the manufacture and testing of cellular and tissue-engineered products and in various efforts to promote global regulatory convergence in cell and gene therapy products. Before joining FDA in 2007, Dr. Oh served on the faculty of Tufts University School of Medicine in Boston. He was trained as a cell biologist and biochemist at Massachusetts Institute of Technology, Johns Hopkins University School of Medicine, and the University of Michigan.




Return to the list

Biosketch

Orla O’Shea, Dr Senior Stem Cell ScientistNIBSC, Blanche LanePotters BarZIP code City, (State), Country Herts, UK, EN36qgTel: +44 01707 641336e-mail: [email protected]

Dr. Orla O’Shea joined the UK Stem Cell Bank in 2011. During her time at UKSCB, she has worked on several large collaborative international projects including, ESNATS, ScrTox and IS-CI3. For the past 4 years she has lead the UKSCB work packages on quality control and train-ing for the EBiSC project. She has also experience banking clinical grade cell lines. She leads the Advanced therapy division work on generation of standards, including work on hPSCs and MSCs. She is also involved in the set up and running of GMP-iPSC reprogramming courses at UKSCB and in partnership with Harvard and Sanger Institutes.




Return to the list

Abstract

Orla O’Shea, Dr Devising assays and standards for cell therapies

The Division of Advanced Therapies at NIBSC is the home of the UK Stem Cell Bank. The Bank collects, archives, and distributes all human ES lines produced in the UK—plus a number from overseas—and makes them available for researchers and developers. We are currently generating a series of hES lines in GLP facilities to EUTCD-grade, to act as starting material for the production of cellular therapies.

In conjunction with our role as a repository for human pluripotent stem cells, we are the leading producer of WHO standards, responsible for the production of roughly 85% of all such standards world-wide. We are well placed, therefore, to coordinate the production of clinical grade materials with our experience in the production of standards and cell assays towards the clinical development of cell therapies.

In this presentation, I shall outline our work in the production of pluripotent cells and their derivatives, the generation of data portfolios to support regulatory submissions of those cells, and our first steps towards the generation of physical standards for cell therapies.




Return to the list

Biosketch

Martin Pera, PhD Professor INTERNATIONAL STEM CELL INITIATIVE/THE JACKSON LABORATORY600 MAIN STREETBAR HARBOR, ME 04609 USATel: +1 207 288 1443e-mail: [email protected]

Martin Pera received his BA from the College of William and Mary, and his PhD from George Washington University, and undertook postdoctoral training in the UK at the Institute of Cancer Research and the Imperial Cancer Research Fund. He held independent research positions at the Institute of Cancer Research and the Department of Zoology at Oxford Uni-versity before joining Monash University in 1996. In 2006 he moved to Los Angeles as the Founding Director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of Southern California. He returned to Melbourne in 2011 to become Professor of Stem Cell Sciences at the University of Melbourne and Program Leader for Stem Cells Australia, the Australian Research Council Special Research Initiative in Stem Cell Sciences. He joined the Jackson Laboratory in 2017.Pera’s research focus is the cell biology of human pluripotent stem cells. His laboratory at Monash University was the second in the world to isolate embryonic stem cells from the human blastocyst, and the first to describe their differentiation into somatic cells in vitro. Currently his lab studies the regulation of self-renewal and pluripotency, heterogeneity in pluripotent stem cell populations, and neural specification of pluripotent stem cells. He has provided extensive advice to state, national and international regulatory authorities on the scientific background to human stem cell research, and has delivered hundreds of commen-taries for print and electronic media on stem cell research, ethics, and regulatory policy.




Return to the list

Abstract

Martin Pera, PhD Genetic and epigenetic stability of human pluripotent stem cells

International Stem Cell Initiative/The Jackson Laboratory

It is well known that human pluripotent stem cells (hSPC) can acquire genetic and epigenetic changes during long-term culture, including numerical and structural chromosome altera-tions, small INDELS and copy number variations, point mutations, and alterations in imprinting and X-inactivation status. Many of the recurrent genetic changes observed in the cultured cells, such as mutations in P53, are also associated with human cancer. While the impact of some of the common genetic alterations on the survival, growth and differentiation of hPSC in vitro has been described, the significance of these genetic variants for the behavior of hPSC in vivo is less well understood. For cell therapy, a key question for safety assessment is whether genetic variation acquired in vitro might result in the neoplastic transformation of differentiated cells intended for therapeutic use in vivo. There is even less experimental data to address this critical point. Clinical findings from studies of human germ cell tum-ors provide some insight into the biology of human pluripotent cells and their differentiated derivatives in the human in vivo. Experimental data on xenografts of hPSC highlight some areas of concern, and reveal some significant gaps in our current understanding. The Inter-national Stem Cell Initiative has formed a Genetics and Epigenetics Study Group to carry out ongoing assessment of the impact of genetic and epigenetic change on research applications of hPSC, in order to devise guidlelines for best practice for maintenance of genetic integrity in research cell lines, and to advise on the assessment of the implications of genetic change for cell therapy. The Group intends to establish a database of recurrent genetic aberrations found in hPSC. This database will help us to understand factors that predispose to genetic instability, to assist in the design of sensitive assays for commonly observed changes, and to help guide in the assessment and interpretation of the likely biological impact of genetic change in hPSC culture.




Return to the list

Biosketch

John C Petricciani Immediate Past President Board Member

John Petricciani is immediate past president of the International Alliance for Biological Standardization (IABS), a non-profit organization devoted to scientific and medical advance-ment of biologicals. He also serves on the World Health Organization (WHO) Expert Panel on Biologicals, is an adjunct staff member at the John Wayne Cancer Institute, and is an honor-ary professor of the Institute of Medical Biology at the Chinese Academy of Medical Sciences, China.Dr. Petricciani currently is licensed to practice medicine in California and Washington, D.C., and has held senior research, medical, and administrative positions in the public and private sectors, including Genetics Institute and the WHO, where he was the chief medical officer of the Biologicals unit. Dr. Petricciani also previously served as the director of the Office of Biologics at the U.S. Food and Drug Administration (FDA).Dr. Petricciani received a bachelor of science in chemistry from Rensselaer Polytechnic In-stitute, a master of science in chemistry from the University of Nevada, and a doctorate in medicine (MD) from Stanford University. He is a fellow of the Royal Society of Medicine (UK) and has authored or co-authored more than 160 articles on tumor cell assays, cytogenetics, and regulatory policy.




Return to the list

Biosketch

Gary M. Pigeau, PhD Development Manager GE Healthcare CATCT @ CCRM661 University Ave.Suite 1002M5G 1M1 Toronto, ON, CanadaTel: +1 416 946 8852e-mail: [email protected]

Gary Pigeau received his Ph.D. in Biotechnology from Brock University in St. Catharines, Ontario. He completed a postdoctoral fellowship at the University of Alberta with a visiting scientist appointment at the University of Oxford. Gary moved to private industry in 2008, where his research group focused on process development and scale-up of a proprietary bioprocess technology. He then moved to commercial, large-scale biomanufacturing in 2013. Gary joined GE Healthcare and the Centre for Advanced Therapeutic Cell Technologies (CATCT) at CCRM in 2016 and leads the pluripotent stem cell (PSC) process development, scale-up and manufacturing efforts.Early clinical successes with PSC-derived, retinal pigment epithelium cells were supported by traditional adherent tissue culture methods. However, many cell types under consideration (cardiomyocytes, hepatocytes, neuronal and pancreatic progenitors, etc) will require higher cell numbers per dose for their respective indications. Stirred-tank reactors (STRs) for the large-scale expansion of PSCs have been reported by several groups and have the potential to generate clinically relevant amounts of cells. Dr. Pigeau’s group at CCRM has developed a fully-closed, scaled-up PSC expansion STR seed train, able to produce ≥1010 PSCs and has demonstrated differentiation of these cells to functional cardiomyocytes.




Return to the list

Biosketch

Anthony Ratcliffe, PhD Head, Center of Excellence LifeNet Health1864 Concert DriveVirginia BeachVA 23453, USATel: 757 609 4627e-mail: [email protected]

Anthony Ratcliffe, Ph.D. is Head, Center of Excellence for LIfeNet Health, an allograft and regenerative medicine company. Synthasome has an active R&D program with a pipeline of products feeding their Sales and Marketing portfolio presently focused on tendon and soft tissue repair. Dr. Ratcliffe obtained his B.Sc. in biochemistry in 1977, and Ph.D. in immunolo-gy in 1980, from the University of Birmingham, UK. He then joined The Kennedy Institute for Rheumatology, London as a Research Scientist, and in 1987 he moved to Columbia University, New York, as Associate Professor of Orthopaedic Biochemistry. In 1996 he joined Advanced Tissue Sciences (then a leading tissue engineering company), where he served as Vice Pres-ident for Research until 2002, when he founded Synthasome, a biotechnology company in San Diego specializing in orthopaedic devices and orthobiologics, where he was President and CEO. Dr Ratcliffe joined LifeNet Health in 2018. Dr. Ratcliffe has focused his work on musculoskeletal research, tissue engineering and regenerative medicine, and the translation of these technologies to products. He has served as a member of the Board of Directors of the Orthopaedic Research Society, Study Sections for NIH, Co-Chairman of the Grant Review Committee for the Orthopaedic Research and Education Foundation, Co-Chairman of the Tis-sue Engineered Medical Products Committee for ASTM, is a Fellow of the American Institute of Medical and Biological Engineering, has published more than 100 papers, and is an inven-tor of multiple patents.




Return to the list

Biosketch

Yoji Sato, Ph.D. Head of Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Japan

Dr. Yoji Sato is Head of Division of Cell-Based Therapeutic Products, Japan National Institute of Health Sciences. Dr. Sato is also an Adjunct Professor of Graduate School of Pharmaceuti-cal Sciences, Nagoya City University, a Guest Professor of Graduate School of Pharmaceutical Sciences, Osaka University, and an Adjunct Professor of Graduate School of Pharmaceutical Sciences, Kyushu University. He received his Ph.D. in Pharmaceutical Science from the Uni-versity of Tokyo in 1995. While a post-doctoral fellow at the University of Cincinnati College of Medicine, he succeeded in establishing a variety of useful transgenic animal models to elucidate mechanisms of cardiac excitation-contraction coupling and heart failure. Dr. Sato’s current research area is in the field of regulatory science for the quality and safety of cell-based therapeutic products (CTPs). He is currently a leader of MEASURE Project, a public-pri-vate partnership initiative for validation of test methods for tumorigenicity assessment of CTPs, as well as a member of the Committee of Cell Therapy- TRAcking, Circulation & Safety (CT-TRACS) of the Health and Environmental Sciences Institute (HESI). He is also serving as a member of Technical Committees, Panel on Science and Technology, Health Science Council, the Ministry of Health Labour and Welfare, and as the Chair of the Database Committee of the Japanese Society for Regenerative Medicine, which is developing a nation-wide database for clinical researches and post marketing studies of CTPs.




Return to the list

Abstract

Yoji Sato, Ph.D. HESI CT-TRACS: an international platform for discussions on tracking, circulation and safety of cell therapy products

Cell therapies show great therapeutic promise in the fields of regenerative medicine and im-munotherapy. To realize their full clinical potential there is a need for greater understanding of their mechanism of action, target delivery and safety of cell-derived therapies, for which there are several existing and many emerging tools. However, adoption of these tools by investigators has been limited. Furthermore, the regulatory landscape is not clearly defined for these emerging therapies.The Health and Environmental Sciences Institute (HESI) recently launched a multi-sector collaborative committee to identify key needs for assessing the safety of cell therapies and identify opportunities to meet these needs. This program, the Cell Therapy - TRAcking, Circu-lation, & Safety (CT-TRACS) committee, provides a neutral platform for cell therapy develop-ers, researchers, regulators, and other stakeholders to interact, discuss current challenges and identify best practices to ensure that these therapies are safe and effective for use. Since its inception in late 2015, CT-TRACS gathered more than 60 members from 25 organi-zations across the United States, Europe and Japan. The committee’s initial goals have been to: 1) evaluate current cell-based therapies safety assessment practice and tools; 2) develop best practices for application of available tools for safety assessment of cell therapies and/or identify gaps in safety assessment; 3) organize a scientific sessions and workshops to present findings of the two committee’s sub-teams and develop recommendations for next steps; and 4) initiate a manuscript describing the needs and gaps identified, to build confi-dence in safety assessment approaches for clinical cell therapy applications. Particularly regarding the safety assessment, the Tumorigenicity sub-team of CT-TRACS is evaluating the translational utility, reliability and predictive value of existing tools and tech-nologies for assessing the tumorigenicity potential of cell-based therapies, through collab-oration with “MEASURE”(*), a public-private partnership initiative, which is led by CT-TRACS members in Japan and is validating various methodologies both in vitro and in vivo for the ability to detect tumorigenic cellular impurities and tumorigenicity of cell therapy products, to identify and share scientific points to consider regarding the applicability and predictivity of these test methods.

* MEASURE: Multisite Evaluation study on Analytical methods for non-clinical Safety assess-ment of hUman-derived REgenerative medical products




Return to the list

Biosketch

Gerald G. Schumann Head of SectionPaul-Ehrlich-InstitutPaul-Ehrlich-Strasse 51-5963225 Langen, GermanyTel: +49-6103-773105Fax: +49-6103-771280e-mail: [email protected]

Gerald G. Schumann obtained his PhD in the field of Biochemistry/Molecular Biology from the University of Erlangen-Nürnberg in Germany. He is currently serving as Head of the Section ‘Human Transposable Elements’ and Assessor for the Section ‘Tissue Engineering/Somatic Cell Therapeutics’ at the Paul-Ehrlich-Institute, the Federal Institute for Vaccines & Biomedi-cines in Langen, Germany. Dr. Schumann is also Adjunct Professor for Genetics and Molecular Biology at the Goethe-University of Frankfurt/Main, Germany. His primary interests include genetic and epigenetic regulation of human endogenous transposable elements (TEs) in the genome of pluripotent stem cells, and the consequences of TE mobilization for genomic integrity. Dr Schumann has published more than 40 papers on the activity of endogenous TEs and serves as editor for the journal ‘Mobile DNA’.After he had received a postdoctoral fellowship award by the Deutsche Forschungsgemein-schaft (DFG) in 1994, Dr. Schumann worked for 5 years as a fellow in the Department of Mo-lecular Biology & Genetics at the Johns Hopkins University School of Medicine in Baltimore, MD, USA. Having received a habilitation scholarship by the DFG in 1999, he started his own laboratory as principal investigator at the Heinrich-Pette-Institut for Experimental Virology & Immunology at the University of Hamburg, Germany. Dr. Schumann was an organizer of the FASEB Summer Research Conferences on Mobile Elements in Mammalian Genomes from 2007 to 2011 and acted as keynote speaker at the 14th International Congress on Transpos-able Elements in Clermont-Ferrand, France in 2006.




Return to the list

Biosketch

Mercedes Serabian, M.S., DABT Chief, Pharmacology/Toxicology Branch 1 (PTB1)FDA/Center for Biologics Evaluation and Research (CBER)Office of Tissues and Advanced Therapies (OTAT)

Mercedes Serabian holds a M.S. degree in Toxicology and is a Diplomat of the American Board of Toxicology (DABT). She currently serves as Chief of Pharmacology/Toxicology Branch 1 in the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evalua-tion and Research (CBER) at the USFDA. She is responsible for overseeing the pharmacology/toxicology regulation, review, and policy development for cellular and gene therapy products and protein therapeutics submitted to OTAT/CBER. She has provided expert pharmacology/toxicology advice on multiple FDA guidance documents. Examples include: xenotransplan-tation, cancer vaccines, cellular therapies for cardiac disease, cartilage repair/replacement products, long-term follow-up of subjects administered gene therapy products, and viral shedding. Ms. Serabian championed the 2013 Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products, outlining FDA recommendations on preclinical data to support clinical studies of cellular and gene therapy products. She has participated in expert working groups to generate various guidelines under the auspices of the International Conference on Harmonisation (ICH). In addition to representing OTAT/CBER at multiple meetings and workshops, she has given presentations on the preclinical regulato-ry considerations for cellular and gene therapies, and participated in the writing of regulatory publications and book chapters.




Return to the list

Abstract

Mercedes Serabian, M.S., DABT Tumorigenicity Assessment of Stem Cell-based Therapies: FDA/CBER ConsiderationsChief, Pharmacology/Toxicology Branch 1 (PTB1)FDA/Center for Biologics Evaluation and Research (CBER)Office of Tissues and Advanced Therapies (OTAT)

According to 21 CFR Part 312.23 (a)(8) of the US regulations, sufficient information derived from preclinical pharmacology and toxicology studies is needed in order to support the deci-sion that a clinical trial in human subjects is reasonably safe and scientifically feasible to con-duct. The data resulting from the preclinical studies should support scientific proof-of-prin-ciple and safety for the administration of the investigational product in the specified clinical population. In addition, preclinical studies help guide the design of certain elements of a clin-ical trial. The potential for tumorigenicity is an important consideration for stem cell-based therapies. The FDA/CBER Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013) includes recommendations for preclin-ical tumorigenicity evaluation of cellular therapy products. Using this guidance document as a platform, this presentation will provide a general overview of the current FDA/CBER con-siderations for the preclinical tumorigenicity assessment of stem cell-based investigational products to support first-in-human clinical trials.




Return to the list

Biosketch

William Shingleton BSc, PhD GE Healthcare Life SciencesSovereign HouseVision ParkCambridge CB24 9BZ United KingdomTel.: +44 (0)7775 [email protected]

Biological Scientist, with a research background in inflammation, biology of ageing and connective tissues. Applying this research in the fields of auto-immune and degenerative diseases. Experience gained in academia at the Universities of Cambridge and Newcastle-up-on-Tyne, combined with 15 years of industrial research with Unilever R&D and GE Healthcare. Recent roles have been focussed on supporting the Cell Therapy Industry through and the application of in-vivo imaging to enable safety, efficacy and MoA studies and development of tools and technology for manufacturing and cryo-preservation.




Return to the list

Abstract

William Shingleton BSc, PhD Preservation and cold chain strategies for cellular therapies

Background. For many cell-based therapies the long-term business model assumes timely delivery of a consistently reliable and effective therapy from the manufacturing site to the point of clinical use. Successful cryopreservation together with an effective cryochain of stor-age and supply are essential elements for making such deliveries. Issues. In addition to the research and development necessary to ensure a clinically effec-tive cryopreserved product there are regulatory issues that must be accommodated, as cells for parenteral application (administered by injection) are treated as medicines. These issues include:• Minimised potential for contamination of the sample.• Reproducibility – all samples to have the same viability and efficacy on thawing.• Traceability throughout the entire cold chain, right up to the patient.Approach being takenContamination of cryopreserved samples can be minimised using hermetically sealed con-tainers (cryovials and bags) and the avoidance of liquid nitrogen in the cryochain.Reproducibility during freezing, including sample to sample variation within an individual run and run to run variation can be reduced by conduction cooling of the samples. Dry thawing with close process control reduces variation during the thawing process.Digital tracking of all process equipment (controlled rate freezers, long term storage vessels, shipping containers and thawing equipment) in the cold chain ensures that the appropriate conditions have been maintained. ConclusionsA complete, liquid nitrogen-free, cryochain now exists. Within this novel cryochain the pre-cise condition in which samples, and clinical products, have been subjected to can be moni-tored and traced in real time.




Return to the list

Biosketch

Glyn Stacey Professor International Stem Cell Banking Initiative

Glyn has a background in microbiology and cancer research. He has also worked on the development of cell substrates for manufacture of biological medicines. He led the UK Stem Cell Bank at the National Institute for Biological Standards and Control at South Mimms, UK since its inception in 2003. His work has covered safety and quality issues in cell therapy, cells used for manufacturing purposes, development of novel cell-based assays and the de-velopment of genetic reference materials for tissue typing and diagnosis of genetic disorders. These activities have included the need for scale up of preservation techniques and long term storage of DNA and cell lines of various types including human stem cell lines and cells used in bioassays and vaccine production. Glyn has been involved in various publications on best practice in cell culture including the landmark report from the ECVAM GCCP task force by Coecke et al., 2005. Glyn is rapporteur for the WHO Cell Substrates Study Group. He has also been a PI for a number of EC funded consortia working on suitability and standardisa-tion of stem cell lines for toxicology and drug discovery, was instrumental in developing the EBiSC European iPSC bank project and is chair of the scientific advisory board for the Safety and Efficacy Hub of the UK Regenerative medicine Platform. Glyn also serves on a number of other Advisory Boards for other EC funded consortia. Glyn has been a member of the UK Department of Health standing advisory committee for the Safety of Blood Tissues and Or-gans (SaBTO) and was a lead author for SaBTO guidance on safety of donor selection for cell therapy. Since 2007 Glyn has also led the International Stem Cell Banking Initiative on human pluripotent stem cell (hPSC) banking which has published international consensus on han-dling and testing requirements for hPSC lines for research and clinical use. He has been a member of the gene and cell therapy committee of the International Alliance for Biological Standardisation since 2013 and has chaired the scientific committee s for the 3rd and 4th IABS cell therapy manufacturing conferences in London (2016) and Los Angeles (2018).




Return to the list

Biosketch

Dr Stephen Sullivan PhD MBA FRSM GAiT, Global Alliance for iPSC TherapiesEmail: [email protected]

Dr Sullivan earned his PhD at the Roslin Institute (Edinburgh) under Professor Ian Wilmut and Dr Jim McWhir, becoming one of the first researchers in Europe to culture human embryonic stem cells. His work focused on pluripotency induction in human somatic cells.Thereafter, Dr Sullivan worked as a Research Fellow at the University of Cambridge, Harvard University, and UCSD deepening his expertise of other human stem cell types (including in-duced pluripotent stem cells) and their applications for human medicine. While at Harvard, he read ‘How Economics Shapes Science’ by Paula Stefan, which stimulat-ed his interest in the financial, as well as the scientific and medical, hurdles that must be sur-mounted to bring stem cell therapies to the clinic. He also worked for Novartis, dealing with clinical trial management and compliance, to better understand the Industrial perspective on bringing novel therapies to market. Thereafter, he earned an MBA at Trinity College Dublin focusing on risk mitigation within the nascent pluripotent stem cell market. From 2008-2017, Dr Sullivan was the Chief Scientific Officer of the Irish Stem Cell Founda-tion, where working with others, he facilitated the introduction of stem cell legislation into the Irish Program for Government. He is an honorary associate of the Scottish National Blood Transfusion Service, a member of Human Pluripotent Stem Cell Advisory Committee at Uni-versity College Cork, and Chief Editor of ‘Human Embryonic Stem Cells – The Practical Hand-book’ published by Wiley & Sons.In June 2017, Dr Sullivan joined GAiT, a new initiative supporting implementation and clinical application of therapies derived from pluripotent stem cells for the benefit of patients glob-ally. GAiT is supported by an international consortium of organisations including the Cell and Gene Therapy Catapult (London, UK), the Centre for Commercialisation of Regenerative Med-icine (Toronto, Canada), the Korea HLA-typed iPSC Banking Initiative (Seoul, Korea) and the New York Stem Cell Foundation (New York, USA).




Return to the list

Abstract

Dr Stephen Sullivan PhD Developing a global haplobank system for clinical-grade induced pluripotent stem cellsInternational Liaison OfficerGAiT (Global Alliance for iPSC Therapies) - Scottish Office - The Jack Copland Centre

Since the derivation of human induced pluripotent stem cells (iPSCs), there has been much interest in the development of iPSC cell lines suitable to be used as a starting material for the manufacture of novel cellular therapies. Realisation of this objective is contingent on the ability to demonstrate comparability between cell lines derived from different donors (whether autologous or allogeneic), between those derived by different manufacturers, and batch-to-batch consistency. Demonstration of comparability is dependent on agreement on the Critical Quality Attributes (CQAs), i.e. those physical, chemical, or biological properties that typically, should be within an appropriate limit, range, or distribution needed to ensure quality and safety of the product for its intended use. In addition, consideration needs to be given to the assays that should be used to measure these parameters and the standards and tolerances that should be applied. Whilst there is general agreement that CQAs in respect of iPSCs include identity, microbio-logical sterility, genetic fidelity and stability, viability, characterisation and potency, a survey of sixteen facilities involved in iPSC manufacturing showed wide variation in parameters, as-says, and standards highlighting differences between institutions as to what would constitute a clinical-grade iPSC line.Consequently, a series of workshops was convened in order to build greater communal un-derstanding and agreement about what should be considered CQAs for clinical-grade iPSC lines and what Quality Control assays should be applied. The first of these workshops was held in Boston, USA on the 18th June 2017 where it was agreed that the work of the Interna-tional Stem Cell Banking Initiative (ISCBI) provided a critical starting point, but that there were some areas whether further clarification was required. The second was held in Sheffield, UK on the 5th September 2017 and discussed each Critical Quality Attribute (CQA) and applica-ble assays and standards, and whether these should be mandatory, for information only, or not required.This talk outlines the agreed quality standards for clinical-grade iPSCs to be housed in the GAiT haplobank network and also gives detail on human leukocyte antigen (HLA) haplotyping data required for patient donor matching.




Return to the list

Biosketch

Clive Svendsen, PhD DirectorCedars-Sinai Medical Center8700 Bverly Blvd., Suite 8404Los Angeles, California 90048U.S.A.Tel: + 310-248-8072e-mail: [email protected]

Dr. Svendsen did his pre doctoral training at Harvard University and received his PhD from the University of Cambridge in England where he then established a stem cell research group before moving to the University of Wisconsin in 2000 to became Professor of Neurology and Anatomy, Director of an NIH funded Stem Cell Training Program and Co-Director of the University of Wisconsin Stem Cell and Regenerative Medicine Center. In 2010 he moved to Los Angeles to establish and direct the Cedars-Sinai Regenerative Medicine Institute which currently has 15 faculty members and approximately 100 staff. One focus of his current research is to derive cells from patients with specific disorders which can then be “repro-grammed” to a primitive state and used as powerful models of human disease. Dr. Svendsen led the first groups to successfully model both Spinal Muscular Atrophy and more recently Huntington’s Disease using this technology. The other side of his research involves cutting edge clinical trials. He was involved with one of the first growth factor treatments for Par-kinson’s Disease and is currently working closely with neurosurgeons, neurologists and other scientists to develop novel ways of using stem cells modified to release powerful growth factors to treat patients with neurological diseases such as ALS, Huntington’s, Alzheimer’s and Parkinson’s.




Return to the list

Abstract

Clive Svendsen, PhD Taking neural progenitors and iPSC cells to the clinic for ALS and Retinitis Pigmentosa: Two case reports

The Svendsen lab has been working for over 15 years to develop a combined fetal neural stem cell and gene therapy approach to treat ALS and Retinitis Pigmentosa. In addition the Cedars-Sinai iPSC core has developed novel ways to generate iPSCs that show very low karyotypic abnormalities and high stability from whole blood. Here were present two case reports based around these cellular products. Case 1: In October 2016 we were given FDA approval to conduct an 18 patient study funded by CIRM involving human neural progeni-tor cells isolated from fetal cortex and engineered to release GDNF. We are over half way through the clinical trial and have established a robust methodology for delivering these cells to the patient. The lead up to the trial (CMC and pre-clinical studies), execution and prelim-inary trial data will be presented. Case 2: The same fetal neural stem cell product has been shown to survive sub retinal injection into the eye and the cells were found to migrate and form a psudo retinal pigment epithelial layer – and protect retinal cells from degeneration in a number of rodent models of eye disease. In collaboration with Dr. Shaomei Want at Ce-dars-Sinai we are about to submit a new IND to the FDA to take this into a Phase I clinical trial in patients. We are now transitioning both programs to an allogenic or autologous iPSC based neural progenitor cell product and will report on progress in this area.




Return to the list

Biosketch

Jean-Hugues Trouvin Professor University Paris Descartes, School of PharmacyDepartment of Health Product and Public HealthHead of the Unit for Pharmaceutical Development and InnovationHead of the Research and Development Department, Central Pharmacy of the Parisian Hospital Group

Professor Jean-Hugues Trouvin graduated in Pharmacy and received his State Doctorate in Pharmacology from the University of Paris. While working as Professor of Pharmacology and Pharmacokinetics at the Faculty of Pharmacy, University of Paris he has also been work-ing as assessor and expert for the French Health authorities since 1986. In France, he was chairman of the French biotechnology working party from 1989 to 1993. He was Director of the Directorate for Evaluation of Medicinal products and Biologics at the French medicine agency (AFSSAPS) from 2001 to July 2007. At the European level, he has been working in the biotechnology/pharmacy working party (BWP) as French representative, since 1986. He has been elected as Chairman of the BWP and reelected for three new terms, he completed his mandate in February 2014. He was the French representative for the Committee for Ad-vanced Therapy medicinal products (CAT) from its opening (2009) to Sept. 2012. He has been involved in the drafting of many guidelines, concept papers and part of the EU regulation and technical requirements for biologicals, biotechnology-derived products, biosimilars and lastly the advanced therapy medicinal products.




Return to the list

Biosketch

Bao-Zhu Yuan, MD, PhD National Institutues for Food and Drug Control (NIFDC)2# Tiantan Xili, Dongcheng District, Beijing, ChinaBeijing, 100050ChinaTel: +011-86-1067095415Fax: +011-86-1065113538e-mail: [email protected]

Dr. Yuan obtained his doctorate degrees in Cell Biology and Oncology in 1994. Since then, he has conducted cell biology and molecular biology studies for over 20 years for addressing the issues regarding tumorigenicity, oncogenes/tumor suppressor genes, (cancer) stem cells, biomarkers, new cancer therapeutic targets, and cancer stem cells, sequentially in Chinese Academy of Medical Sciences (1994-1995), National Cancer Institute (NIH, USA, 1995-2000), National Institute for Occupational Safety and Health (CDC, USA, 2000-2010), and Beijing Shiji-tan Hospital (CMU, 2010-2011). In October 2011, Dr. Yuan was recruited by the NIFDC/China FDA (CFDA) as a ‘Global Talent’ to take the current position, the director and professor of the Cell Collection and Research Center (CCRC). During past 6 years, Dr. Yuan has directed various quality control studies for advancing NIFDC/CFDA’s capacities in regulating different types of therapeutic cells. Dr. Yuan has being actively involved in drafting and revising the “Guidelines for quality control and preclinical studies of stem cell-based medicinal products”, which was promulgated jointly by CFDA and HFPC in August 2015 and, since then, has been serving as a key member of a new regulation committee for ‘Clinical Studies’ of stem cells in China. In addition, within the Chinese NRL, i.e. the National Institutes for Food and Drug Control (NIFDC), Dr. Yuan has been taking the responsibility of establishing a quality control system as well as applying the sys-tem to conduct quality assessment of different therapeutic cell products for various product developers in China.




Return to the list

Biosketch

Kathryn C. Zoon

Dr. Kathryn C. Zoon is currently NIAID/NIH Scientist Emeritus, NIH. She was recently appoint-ed to the Board of Directors of Emergent Biosolutions, Inc and the FDA Alumni Association. She is also a member of the National Academies of Science Division of Earth and Life Studies Advisory Board (2015-current). Previously she was Interim Director of the new NIH Office of Research Support and Compliance. She was also Chief of the Cytokine Biology Section in the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH (2004-2016), where she conducted research on the structure and function of human interferon alphas and developed a new cell therapy using IFNs and autologous monocytes for ovarian cancer. She was previously the Director of the Division of Intramural Research at NIAID (2006-2015). Dr. Zoon served as the Principal Deputy Director of the Center for Cancer Research at the National Cancer Institute, 2003–2004. Dr. Zoon was the Director of the Divi-sion of Cytokine Biology in CBER, 1988–1992, where she directed the research and review of cytokines, growth factors, and cellular products and from 1992-2003 she was the Director of CBER, FDA. She received her B.S. degree, cum laude, in chemistry from Rensselaer Poly-technic Institute and her Ph.D. in biochemistry from the Johns Hopkins University. Dr. Zoon is the author of more than 140 scientific papers. Dr. Zoon has been a member of the National Academy of Medicine since 2002 and served a member of the WHO’s Expert Committee on Biological Standardization for almost two decades.




Return to the list

4th cell therapy conference : manufacturing and testing of...

Documents