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In the first of two sessions centered on the COVID-19 pandemic, our focus will be on pathogenesis and on experiences of health care workers on the front lines in Italy, New York City, and China. ISCT members have been at the forefront of both clinical care and in clinical and mechanistic investigations. An outstanding panel of global speakers has been assembled and there will be ample time for discussion.
Session will be followed by a 30 minute Open Discussion
Chair: Sowmya Viswanathan (CA)
Session Description: This session will bring together speakers who will provide a full spectrum overview of latest developments in the field of mesenchymal stromal cell research. This includes insights into newly hypothesized mechanisms of action and single cell characterization of mesenchymal stromal cells, clinical translation challenges using pooled bone marrow-derived mesenchymal stromal cells for treatment of refractory Graft-vs. Host Disease, and updates from a pioneering European trial on the use of mesenchymal stromal cells to treat refractory Sclerodoma.
Jacques Galipeau (US)
Focusing on evolving thinking on new discoveries regarding MSC endogenous single cell biology, exosomes, matrix functionalities, potency measurement and variables affecting potency (especially in the immune modulation space), we propose that an overlooked and potentially disruptive perspective is the impact of in vivo persistence on potency which is not predicted by the surrogate cellular functional assays performed in vitro and how this translates to in vivo outcomes. We propose a theory that MSC Potency (P) writ large is proportional to in vivo persistence (p) of said exogenous pharmaceutical MSC: P a p. We further develop this theory in the following: that persistence (p) is the product of 3 variables (in ranked order): route of delivery (r), functional fitness (f), and dose (d). Therefore, (a) P a p and (b) p a r∙f∙d.
Halvard Bönig (DE)
Using a proprietary pooling method, Bader, Kuci, and the presenting author are generating off-the-shelf cryopreserved MSCs of pharmaceutical quality – with dose-to-dose equipotency and a highly robust, GMP-compliant manufacturing process. Preliminary evidence after treatment of 92 children, adolescents and adults indicates excellent tolerability and suggests efficacy. Responses were better if treatment was early, but remained clinically meaningful even at later time points. Survival after 6 months was similar for adults and children, seemed superior to survival of similar patients treated with any of the alternative medicines. A multicentric international randomized trial against best available treatment is expected to begin recruitment in Q2/2020 with the goal of obtaining a marketing authorization in Europe.
Dominique Farge (FR)
Systemic sclerosis (SSc) is an autoimmune disease with high morbidity and mortality. SSc treatments are only palliative, except autologous hematopoietic stem cell transplantation which indication remains limited to selected patients. Mesenchymal stromal cells (MSC) modulate key mechanisms driving SSc (i.e. endothelial cell damage, immune activation, inflammation and fibrosis).
Co-Chairs: Bruce Levine (US) and Christian Chabannon (FR)
CAR-T Cells represent the first example of a cellular therapy that has moved from immunological concepts developed in research laboratories to worldwide and large-scale industry-manufacturing of potent therapeutic agents. The bumpy road for these developments exemplify the many scientific challenges that await developers of this class of therapeutics. While scientific developments continue to occur at a high pace for CAR-T and CAR NK therapies, the race to solve the logistical, medical, financial and societal issues is engaged, with the goal to bring this class of therapeutics to all patients in need of them. CAR-T and CAR NK Cells will likely pave the way for other forms of immune cellular therapies, but also for regenerative medicines.
Marcela Maus (US)
- Describe the limitations of current generation CAR T cells
- Describe some of the techniques and approaches to multi-targeted CAR T cells
- Understand the role of the tumor microenvironment and its interactions with T cells
Stefan Radtke (Us)
Hematopoietic stem cell (HSC) gene therapy is a promising treatment option for various hematological diseases and disorders. Most currently available approaches target CD34+ cell–enriched fractions, a heterogeneous mix of mostly committed progenitor cells and only very few true HSCs with long-term multilineage engraftment potential. Consequently, gene therapy approaches are limited in their HSC targeting efficiency and very expensive due to the large quantities of modifying reagents needed. In addition, exposure of non-target cells to lentiviral vectors or nucleases can increase the risk of unwanted side-effects in these cell populations.
We aimed to develop a clinical protocol to reliably purify and efficiently gene-modify human HSC-enriched CD90+ cell fractions, which ultimately would allow us to reduce costs without compromising in vivo engraftment.
Large-scale enrichment of CD34+ cells from GCSF-mobilized leukapheresis products was initially performed on Miltenyi Biotec’s CliniMACS Prodigy®. Yield, purity, quality, and feasibility of CD90+ cell sorting was then tested on the jet-in-air sorter FX500 from Sony and the cartridge-based closed-system sorter MACSQuant® Tyto® from Miltenyi Biotec. Transduction was performed using a clinical-grade, GFP-encoding lentivirus. Engraftment was tested using the NSG mouse xenograft model.
Purity and yield after flow cytometric sorting of CD90+ cells were similar with either the FX500 or MACSQuant® Tyto®. Both approaches reliably reduced the overall target cell count by 10- to 15-fold without impacting the cells’ viability and in vitro colony-forming cell potential. Transduction efficiency of sorted CD90+ cells was significantly improved compared to bulk CD34+ and especially the CD34+CD90+ subset. All cell fractions demonstrated robust mouse xenograft potential. Significantly higher levels of GFP expression in peripheral blood, bone marrow, spleen, and thymus were observed after transplantation of gene-modified CD90+ compared to bulk CD34+ cells in NSG mice.
Antonio Pérez‐Martínez (ESP)
NKG2D is a C‐type lectin‐like transmembrane activating receptor present on the surface of natural killer (NK) cells, NKT cells, CD8+TCRγδ+ T cells, and certain subsets of CD4+ T cells. Biogenesis of NKG2D ligands (NKG2DL) is stimulated in cells under stress conditions such as viral infection, cellular senescence, and tumorigenesis. NKG2DL are expressed on various tumor types including different pediatric solid and hematological malignancies, thus providing suitable targets for cancer therapy. NKG2D activation on NK cells results in cytokine secretion and exocytosis of cytotoxic granules.
NKG2D is particularly relevant for cancer immunosurveillance: Interaction between NKG2DL and NKG2D receptor is essential for NK cell–mediated elimination of osteosarcoma tumor‐initiating cells. However, tumor cells can develop various immune escape strategies. Nevertheless, the use of NKG2D‐CAR on memory CD45RA– T cells may overcome these limitations. We have shown that NKG2D‐CAR–expressing CD45RA– T cells were cytotoxic against three osteosarcoma cell lines and 8/10 leukemia cell lines with specific lysis of over 50%. Myeloid and T‐ALL cell lines were more susceptible (specific lysis ranging from 50–78%) than B‐ALL cell lines (19–52%). NKG2D‐CAR+ memory CD45RA– T cells also had considerable antitumor activity in a mouse model of human osteosarcoma, whereas non-transduced T cells were ineffective.
We have developed a protocol to expand clinical-grade NKG2D‐CAR–expressing memory CD45RA– T cells in a fully automated closed system, CliniMACS Prodigy®. This expansion protocol allowed us to obtain up to 2076±697 million cells with 77.8±20% NKG2D‐CAR expression and 76±10% viability. Harvested CAR T cells showed specific lysis of Jurkat cells (90±14%) and 531MII osteosarcoma cell line (31±16%). Vector copy number was ≤5 in all validations. CGH and karyotype showed no genetic alterations. Free viral particles were undetectable in the supernatants. No overexpression of MYC/TERT was found except for one validation. Endotoxins were ≤0.25 EU/mL. Automated manufacturing of clinical‐grade NKG2D‐CAR–expressing memory CD45RA– T cells using the CliniMACS Prodigy® is feasible and reproducible. We plan to explore different clinical trials on pediatric diseases.
Annelise Bennaceur Griscelli (FRA)
The breakthrough discovery of induced pluripotent stem cells (iPSCs) is currently profoundly modifying the landscape of cell therapy and allows us to open novel perspectives for the generation of advanced therapy medicinal products (ATMP) potentially applicable in all fields of medicine. In terms of a large-scale therapeutic landscape, implementation of iPSC-derived allogeneic therapies will require suitable immune-HLA-matched iPSC lines from healthy universal donors and/or the derivation of hypoimmunogenic iPSC lines. To anticipate future demands in effective allogeneic therapies, the availability of accessible cost-effective and safe iPSC lines is a major requirement, to provide off-the-shelf unlimited numbers of therapeutic products from a single iPSC master cell bank. We have previously developed several research-grade master banks of human iPSCs using an in vitro expansion workflow. However, several hurdles remain for industrial, cGMP-grade, large-scale production and banking of these cells.
We report a procedure using the integrated GMP-compliant cell processing platform CliniMACS Prodigy® providing automated cell feeding and harvesting in a closed system. The iPSC clone used on the CliniMACS Prodigy Platform was previously derived from a healthy donor using the CytoTune™- iPS 2.0 Sendai Reprogramming Kit, manufactured according to GMP principles, on StemMACS™ iPS-Brew XF, human medium and human recombinant laminin matrix. Over 14 in vitro cell passages, this cell line was replated and expanded on the CliniMACS Prodigy Platform within 2 weeks. At the end of the process, 1.4 billion iPSCs were collected with a high genetic stability as evaluated by karyotyping and CNV/NGS analysis before and after scalable expansion. Expanded iPSCs maintained their pluripotency markers and an efficient differentiation towards endodermal, mesodermal, and ectodermal trilineage layers. Overall, this process provides a safe and standardized scalable manufacturing platform for GMP-iPSC master cell banks. The feasibility of this procedure opens novel perspectives in large-scale production of mesenchymal stem cells and immunocompetent cells for our therapeutic program.
Organized by the ISCT Cardiovascular Scientific Subcommittee, this session will shine a spotlight on pluripotent stem cells as a promising therapeutic approach to cardiovascular diseases and highlight both pre-clinical and clinical research currently being undertaken to drive the translation of iPSC-based regenerative medicine. The session will conclude by featuring a series of top scoring abstract submissions addressing emerging research in iPSC followed by an interactive Q&A with keynote presenters.
Massimiliano Gnecchi (IT)
The talk will address the rationale for using PSC and more specifically their cardiac-committed derivatives for repairing the heart, their current use in the clinics and the associated technical challenges and the perspective of leveraging their paracrine properties to exclusively deliver their secretome.
Building functional vascular grafts from human pluripotent stem cells-derived endothelial cells (Oral Abstract 1)
Gabor Foldes (UK)
Human vascularised mesenchymal spheroids highlight the role of WDR35 in bone formation (Oral Abstract 2)
Loic Fievet (FR)
Human kidney organoids produce functional renin (Oral Abstract 3)
Anusha Shankar (NL)
Unlocking the therapeutic potential of embryonic and induced pluripotent cells, this session will offer novel insights into the use of pluripotent cells in the treatment of neurological and developmental disorders as well as highlight recent advancements towards clinical application of hPSCs for monogenic diseases.
Marc Peschanski (FR)
Derivatives of pluripotent stem cell lines are now tried clinically for regenerative medicine in various pathological indications. I will discuss the scientific bases on which those clinical applications are built and describe their process taken the example of our ongoing trial for retinitis pigmentosa. I will then identify main areas of progress and envision current limitations of those therapies.
The development of the iPS cell technology has revolutionized our ability to study development and diseases in defined in vitro cell culture systems. The talk will focus on the use of gene editing for the study of epigenetic regulation in development and disease.
1. Editing DNA methylation in the mammalian genome: The functional significance of specific methylation events in development and disease remains elusive due to lack of experimental approaches to edit these events. We developed a DNA methylation editing toolbox that fusion of either the catalytic domain of Tet1 or Dnmt3a protein to a catalytic inactive Cas9 (dCas9) to achieve targeted DNA methylation editing with co-expression of target-specific guide RNAs. Our results established that a modified CRISPR system with dCas9 fused by DNA modification enzymes can be assembled into DNA methylation editing tools to study the functional significance of specific methylation event in the mammalian genome. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.
2. Epigenetic regulation and disease: reversal of gene silencing in Fragile X and Rett Syndrome: The expansion of a GGC repeat leads to methylation and silencing of the FMR1 gene, which is the cause for Fragile X Syndrome. We have used the epigenetic gene editing tools to induce hypomethylation the repeat expansion leading to expression of the FMR1 gene and reversal of the disease specific cellular phenotype. In Rett syndrome, the mutation of the X-linked MECP2 gene is causative for the disease. I will discuss our efforts to activate the wt MECP2 allele carried on the inactive X chromosome.
Sandeep Soni (US)
AAV DOWNSTREAM PROCESSING – ARE WE READY FOR INDUSTRIAL SCALE GENE THERAPY? (Oral Abstract 27)
Jessica de Rooij (NL)
In vivo Genome Editing for Vision (Oral Abstract 28)
Jeong Hun Kim (KR)
THE GENETICALLY-ENGINEERED STEM CELL THERAPY OF HUNTINGTON DISEASE: SPT4 KNOCKOUT HD PATIENT IPSC-NPCS TRANSPLANTATION RESCUE ABNORMAL NEURONAL (Oral Abstract 29)
HyunJung Park (KR)
Construction of a Novel, Dual, Self-Replicating Minicircle; an Efficient Tool in Transdifferentiation (Oral Abstract 30)
Naeimeh Rezaei (IR)
This session will analyze the building blocks, opportunities and obstacles faced in the formation of collaborative networks to advance the field of cell-based therapeutics for musculoskeletal disease. The session will begin by addressing the clinical impact of cell heterogeneity and plasticity followed by an overview of European consortia addressing standardized protocols for tissue specific progenitor cell fabrication. The current collaborations in place for clinical trials will also be reviewed. Furthermore, the importance of establishing collaborative networks to investigate, define, and translate tissue specific progenitor cell-based therapeutics for musculoskeletal application will be addressed.
Dr. Karin Tarte will discuss the heterogeneity and plasticity of human mesenchymal stromal cells (MSC) and how it could impact their clinical use. In particular, she will present recent data on the influence of tissue origin, donor characteristics, and culture conditions on the functional features of clinical-grade MSC. Such data paves the way for a better understanding of the critical parameters that could influence the choice of MSC for therapeutic applications.
Christian Jorgensen (FR)
Immune Reprogramming in Human Subjects after Extracorporeal Mesenchymal Stromal Cell Therapy (Oral Abstract 5)
Rita Barcia (US)
Manufacturing Development of SENTI-101, a Gene Circuit Modified Allogeneic Bone Marrow Derived Mesenchymal Stromal Cell (BM-MSC) Therapy for the Treatment of Solid Tumors (Oral Abstract 6)
Philip Lee (US)
Mesenchymal Stromal Cells Alleviates Experimental Acute Respiratory Distress Syndrome through the Cholinergic Anti-Inflammatory Pathway (Oral Abstract 7)
Xiaoran Zhang (CN)
Evaluating the Therapeutic Potential of Bone-Marrow Mesenchymal Stromal Cells and Exercise in a Post-Traumatic Osteoarthritis Model: Functional and Radiographic Analysis (Oral Abstract 8)
Camila Carballo (US)
Engineered nasal cartilage for the repair of osteoarthritic knee cartilage defects (Oral Abstract 9)
Karoliina Pelttari (CH)
Chair: Bernd Giebel (DE)
Most cells release Extracellular Vesicles (EVs) into their environment. In particular, small EVs of 50-200 nm that include exosomes, have been shown to mediate intercellular communication in many physiological and pathophysiological processes. Small EVs from some cell sources, e.g. mesenchymal stromal cells (MSCs), can alleviate pathological processes and are considered as novel therapeutic agents. Within the session basic aspects of EV biology and their therapeutic potential will be discussed.
Clotilde Théry (FR)
Basic aspects of EV biology will be provided and methods to prepare and characterize EVs will be discussed, including the criteria provided by the International Society of EVs (ISEV) as Minimal Information for Studies of EVs 2018 (MISEV2018).
The promising therapeutic potential of MSC-derived small EVs (MSC-sEVs) to treat intractable diseases will be discussed together with the challenges in developing MSC-sEVs into safe, potent therapeutics including requirements to describe their identity and potency.
Dr. Lim will be discussing her lab’s observations on how different donor characteristics such as prematurity, twins vs singletons, gestational diabetes etc influence EV properties and how these have to be considered when evaluating their therapeutic potential.
Recent successes in the market authorization of cell and gene therapy products has generated tremendous excitement. However. to be successful, the industry now needs to move into a phase of industrialization, where like the car industry it needs the “eureka” moment of standardization that allows the efficient flow from product to patient. To realize this, we need to overcome the barriers between all the silos in the system (e.g. hospital, manufacture, testing, etc.) so that patients are efficiently treated.
Cellular therapy has shown high efficacy in the treatment of hematological malignancies by the use of T cells genetically modified by chimeric antibody receptors (CAR). Two CAR T cell products have been approved so far and are applied to patients in defined clinical indications in an industrial scale. However, although many novel approaches are currently followed, this approach has demonstrated less efficacy in the treatment of solid malignancies so far, especially due to limits in defining suitable surface target antigens. Nevertheless, highly suitable target antigens represented by mutated peptide ligands derived from somatic mutations are presented by major histocompatibility complexes (MHC) in most individual cancers which may be identified by mass spectrometry-based approaches. Such epitopes may be recognized by high avidity T cell receptors (TCR) derived from the autologous or allogeneic repertoire. Neoantigen-specific TCR and derivates therefore represent highly attractive tools for genetic modification of non-dysfunctional T cells. The development of cellular therapies using neoantigen-specific TCR-modified effector cells represents a highly attractive therapeutic approach facing, however, major hurdles with respect to regulatory and industrial challenges of clinical translation. Finding solutions for these challenges will be of major importance to provide such therapies to a larger patient population in future.
Alberto Santagastino (CH)
- As the industry moves from clinical to commercial, we are reaching an inflection point and face key challenges.
- Manufacturing is the focus and is under critical pressure from a technical, timeline and cost perspective.
- Process development will be key to industrializing the manufacturing and achieving commercial viability.
- CDMOs have a key role to play in delivering industrialization, technologies, capacity and expertise to the industry
Emanuele Ostuni (CH)
- Basics of CAR T science
- CAR T Supply chain and its requirements
- CAR T business model and approaches
- Basics of value-based healthcare
- Complexity of reimbursement
- Future of CAR T
On completion of this ISCT symposium activity, participants will be able to:
- Understand the biological/preclinical differences between current chimeric antigen receptor (CAR)-T cell therapy options for relapsed/refractory diffuse large B-cell lymphoma, as well as innovations in CAR-T cell therapy under investigation
- Recognize the role of key biomarkers and baseline characteristics in patient selection for CAR-T cell therapy treatment and patient monitoring post-CAR-T cell infusion
Discuss the impact (or lack thereof) of CAR-T cell product attributes on safety and efficacy outcomes
Uwe Platzbecker, PhD
Richard T. Maziarz
Gene-engineering is currently ‘in-vogue’ as a potential treatment for multiple monogenetic and rare diseases. This session will highlight the progress in the field of gene-insertion, vector biology and gene-editing for both the ex-vivo and in-vivo approaches of gene manipulation. The current challenges and safety issues will be discussed, with the spotlight on ongoing clinical trials as examples of potential curative therapies.
Dr. Kohn will review clinical and pre-clinical studies on gene modification of autologous hematopoietic stem cells to treat genetic blood cell diseases.
Fanconi anemia is a rare disease characterized by congenital abnormalities, increased cancer predisposition and early bone marrow failure. Recent results from our laboratory have shown that corrected cells using lentiviral vectors can engraft in the patients in the absence of any conditioning, eliminating potential side effects associated to allogeneic bone marrow transplantation. In this context, gene editing has emerged as a potential strategy to accurately correct specific disease related mutations. Since non-homologous end-joining (NHEJ) is the preferential DNA-repair mechanism in HSCs, particularly in the case of FA cells, we aimed at exploiting this pathway for the compensation of FA associated mutations, mimicking the spontaneous reversions observed in mosaic patients.
Previous experiments conducted in lymphoblastic cell lines (LCLs) showed the ability of NHEJ to correct two different mutations frequently found in FA-A patients. A similar gene editing approach was then used to correct primary CD34+ cells from FA-A patients. Remarkably, NHEJ-mediated editing induced an in vitro proliferative advantage in these cells, as previously shown with lentiviral vectors and also corrected their characteristic FA-cell phenotype. In contrast to HDR, we found that the efficacy of NHEJ to edit primitive human HSCs was comparable to that observed in more mature progenitor cells, indicating that NHEJ-editing approaches should constitute a good approach for the editing of long-term repopulating HSCs.
Moving towards the clinical application of NHEJ-mediated repair we focused on improving gene editing efficiency in HSCs and expanding its applicability to other FA complementation groups. Using chemically modified small guide RNAs (MS-sgRNAs) editing efficacy reached levels of 89% in healthy donor hematopoietic stem/progenitor cells.
To confirm the broader applicability and the efficiency of this approach in other FA complementation groups we selected FA lymphoblastic cells lines (LCLs) harboring mutations in FANCB, FANCC, FANCD1 (BRCA2) and FANCD2. The NHEJ-mediated editing was robustly efficient reaching an 80% editing events with an average of potentially therapeutic indels ranging from 20 to 30%, being particularly remarkable in the FA-D1 subtype, characterized by a marked defect in homologous directed repair (HDR).
All together these results demonstrate that the CRISPR/Cas9 induced NHEJ-mediated editing constitutes a simple and efficient strategy that could be applied for the treatment of specific FA mutations in all complementation groups.
Data will be presented to address key questions in the pre-clinical development of an AAV-based gene therapy
- Proof-of-concept studies demonstrating efficacy in a mouse model of hemophilia A
- Transgene DNA biodistribution in mice
- Changes in the expression profile as a function of age in mice
- Evaluation of germline transmission risk
- Describe the challenges for CAR-T therapies for advanced solid tumors.
- Review the rationale and early experience with prostate specific membrane antigen (PSMA) as a target antigen for CAR-T therapy for advanced prostate cancer.
PROPHYLACTIC TOCILIZUMAB BEFORE CD3/4-1BB ANTI-CD19 CAR-T CELL INFUSION DECREASES INCIDENCE OF SEVERE CRS WITHOUT INCREASED RISK OF NEUROTOXICITY (Oral Abstract 15)
Paolo Caimi (US)
Allogeneic stem cell transplant (HSCT) for acute lymphoblastic leukaemia (ALL) using CD34 selected stem cells followed by prophylactic infusions of pathogen-specific and CD19 CAR T cells (Oral Abstract 16)
Gaurav Sutrave (AU)
NOVEL CAR DESIGN REVERSING THE PD-1 SIGNAL BOOSTS THE EFFICACY OF CAR-T CELLS WITH LOW CYTOKINE RELEASE AND NO OFF-TARGET EFFECT (Oral Abstract 17)
Bin Zhang (CN)
THE CLINICAL STUDY OF ANTI-BCMA CAR-T WITH HUMANIZED SINGLE-DOMAIN ANTIBODY (Oral Abstract 18)
Jishuai Zhang (CN)
A NOVEL SWITCHABLE CAR-T CELL THERAPY FOR TUMOR RETARGETING AND IMPROVED SAFETY (Oral Abstract 19)
Mauro Castellarin (US)
Effect of Allocetra-OTS (off-the-shelf apoptotic cells) Therapy in Sepsis (Oral Abstract 20)
Dror Mevorach (IL)
Modulation of inhibitory receptor signaling pathways improves CAR T cell activity against glioblastoma (Oral Abstract 21)
Khaled Sanber (US)
In the second COVID-19 session, our focus will be on novel cell-based and immunologic-based therapeutics. Again ISCT members have been at the forefront and an outstanding panel of investigators has been assembled. Our goal is to provide a platform of hope for these novel therapeutics as an ideal way to close the LIVE program of the ISCT annual meeting.
This session will be followed by a 30-minute open discussion, and a concluding statement to close off the LIVE sessions of ISCT 2020 Paris Virtual.
There will be a tribute to Luc Sensebé during this session.
Maria Cancio (US)
Immuno-Gene Therapy Approaches
Anti-viral approaches and anti-cytokine storm approaches (anti IL-6, anti IL-1,etc)
Chair: Sai Kiang Lim (FR)
Marion Gimona (AT)
Scalable Production of Human Mesenchymal Stromal Cell (MSC)-Derived Extracellular Vesicles in Microcarrier-based Bioreactors under Xeno(geneic)-free Conditions (Oral Abstract 31)
Miguel Fuzeta (PT)
Bioassay standardization to assess exosomes antiinflammatory activity in vitro (Oral Abstract 32)
Ricardo Malvicini (AR)
THERAPEUTIC EFFECTS OF EXTRACELLULAR VESICLES OBTAINED FROM BONE MARROW-DERIVED, ADIPOSE TISSUE-DERIVED, AND LUNG-DERIVED MESENCHYMAL STROMAL CELLS ON THE LUNG AND DISTAL ORGANS IN EXPERIMENTAL SEPSIS (Oral Abstract 33)
Natalia Blanco (BR)
TRANSFER OF MITOCHONDRIA THROUGH MSC-DERIVED EXTRACELLULAR VESICLES IMPROVES ALVEOLAR-CAPILLARY BARRIER INTEGRITY AND ALLEVIATE MITOCHONDRIAL (Oral Abstract 34)
Johnatas Silva (UK)
Prematurity negatively impacts therapeutic effect of human amnion epithelial cells in experimental bronchopulmonary dysplasia (Oral Abstract 35)
Dandan Zhu (AU)
Chair: Julie Murrell (US)
Life changing therapies are being created and manufacturing systems are constantly evolving. However there also needs to be innovation within the logistical delivery of advanced therapies within the clinical setting. The supply chain is working now but how will it cope when there are tens of therapies and thousands of patients, globally? The “hidden challenge” is the last 100m within the clinical setting.
This session will highlight some key challenges that developers need to be aware of, and present solutions that are currently being developed. Moreover, presenters will describe ways the infrastructure, equipment, staffing, training, and systems need to be designed to operate efficiently to treat the patients.
Jacqueline Barry (UK)
Significant advances in stem cell biology, immunology and genetic engineering have underpinned the emergence of a global industry providing potentially curative treatments targeted at conditions with high unmet medical need. This includes cancer, inherited genetic disorders and chronic degenerative diseases the increasing prevalence of which is associated with an ageing population. The global cell and gene therapy industry is growing rapidly with over 900 therapy developers sponsoring >1000 clinical trials including almost 100 phase III trials across oncology, gastroenterology, cardiovascular disease, central nervous system diseases, ocular and many other indications.
However, ATMPs are considerably different from existing treatments and require new ways of working by both industry and healthcare systems. Increasing complexity of products for a diverse range of clinical conditions, coupled with increased patient demand will bring new challenges. It is estimated 10 licensed products will come to market/annum over the next 5 years alongside an expanding number of clinical trials year on year. This development/expansion of ATMPs will bring challenges of scale-up and -out, and will require new extended supply chains and innovative treatment modalities necessitating unprecedented partnership between healthcare providers and industry – which can only be achieved by cooperative working between all parties from the outset. The integration of new innovation within the healthcare system has the potential to transform the current shepherded delivery to a turn-key industrialised delivery of these life-saving treatments.
UK Regulatory authorities, the NHS and Government are coming together to accelerate access for patients to these life changing medicines with initiatives such as the Advanced Therapy Treatment Centre Network and the Accelerated Access Collaborative which aim to facilitate the innovative a joint working detailed above.
Chris Herbert (US)
Advanced Therapies are making rapid progress towards becoming commissioned as therapeutic options outside the research setting. Whilst much work has gone into shipping patient-specific starting materials and therapies around the world, internal logistics within complex hospital sites remain a challenge. Whilst the current situation is manageable for the relatively small numbers of therapies that are used in commissioned services or research, the challenge of how this would be managed at scale needs to be addressed so that an inability to manage Advanced Therapies within a hospital doesn’t become a blocker to wide scale adoption.
This talk will examine the challenges identified with the chain of custody and management of Advanced Therapies within Leeds Teaching Hospitals NHS Trust, one of the largest providers of healthcare in Europe which operates across a number of different sites. It will look at the challenges associated with product receipt from couriers, management and oversight from the pharmacy team, integration of logistics with the complex care needs of a patient and the moving and handling of received therapies through a large, complex organisation.
Co-Chairs: Khalid Shah (US) and Massimo Dominici (IT)
Previously published studies have shown that different stem cells including MSC home to tumors and thus can be armed with therapeutic transgenes, a strategy that can be used to inhibit tumor growth by selectively inducing apoptosis in proliferating tumor cells. Recently, studies have demonstrated the translational potential of gene edited and engineered stem cells in mouse models of primary and metastatic tumors that mimic clinical settings. This proposed session aims at bringing together investigators who have gene edited and engineered stem cells and demonstrated novel pre-clinical efficacy of engineered stem cells alone or in combination with other immunomodulatory cells in mouse tumor models.
The educational objectives of this session/symposium will be following:
- Multiple approaches in gene editing and engineering of stem cells
- The challenges of applying engineered stem cell in tumor models
- The clinical translation of therapeutic stem cells
Co-Chairs: Basak E. Uygun (US) and Giuseppe Orlando (US)
The GI Hot Topic session features three presentations to introduce the cutting-edge research in regenerative medicine for digestive diseases by the forerunners of the field. These include tissue engineering and cell therapy for gastrointestinal motility, cell therapies for liver diseases and bioengineering approaches to replace liver functions. The session will end with an open forum discussion of what the needs and the next steps are in regenerative medicine in digestive diseases.
Khalil N. Bitar (US)
New acquisitions into liver regenerative medicine: from stem cell niches to clinical applications
Vincenzo Cardinale (IT)
Whole-liver bioengineering: The future of transplantation medicine
Pedro Baptista (ES)
Co-Chairs: Laertis Ikonomou (US) Aaron Levine (US)
The provision of unproven cell interventions sold directly to consumers remains a global challenge, posing risks to patients and complicated the development of safe and effective proven cell therapies. Indeed, despite, or perhaps because of, increased scrutiny from regulatory bodies, the unproven cell therapy industry has evolved rapidly, marketing new interventions, including unproven exosome-based products, and taking advantage of various regulatory pathways, such as expanded access and right-to-try. This panel brings together multiple perspectives on the development of unproven cell therapies to bring audience members up to date on emerging trends in this industry and on the activities and plans of the ISCT Presidential Task Force on the Use of Unproven and/or Unethical Cell and Gene Therapy.
Speculative Cell Banking Services
Aaron Levine (US)
Unproven Extracellular Vesicle Therapies
Eva Rohde (AT)
The ethical and legal issues surrounding accelerated approval and access approaches
Patti Zettler (US)
ISCT Presidential Task Force on the Use of Unproven and Unethical Cell & Gene Therapies Annual General Meeting
Massimo Dominici (IT) & Laertis Ikonomou (US)
Gene therapy of globin disorders is one of next big things to hit the field, due to the size of the candidate populations, the unmet demand that it represents, rapid technological evolutions, and the foreseeable enormous challenges in terms of market access and financial sustainability. This session will address recent advancements in gene therapy for the treatment of hemoglobinopathies and next steps to bring this innovative therapeutic approach to affected patients.
Beta-thalassemia and sickle cell disease are the most prevalent monogenic diseases and are caused by quantitative or qualitative defects in the production of adult hemoglobin. Gene therapy is a potential treatment option for patients lacking an allogenic compatible hematopoietic stem cell (HSC) donor. Over the last fifteen years, gene therapy through the use of genetically modified autologous hematopoietic cells has shown in several clinical trials its powerful outcome to successfully treat globin disorders. Lastly, genome-editing and homologous recombination technologies have undergone spectacular developments over the last couple of decades. In view of the impressive progress reported for the gene-addition strategy, gene-editing approaches to patients affected by globin disorders would move gene therapy one step forward.
Rahul Palchaudhuri (US)
This presentation will summarize recent pre-clinical research to show proof of concept that a single dose of targeted antibody drug conjugate is sufficient to enable HSC-based gene transfer in relevant nonhuman primate model without the need for chemo or radiotherapy.
The objectives of this talk are to describe the various gene-editing platforms currently being investigated for hemoglobinopathies. The presentation will also highlight the differences between gene-insertion and gene-editing platforms and provide an overview of the current trials.
ISCT and the Cord Blood Association (CBA) are pleased to host the ISCT 2020 Cord Blood Workshop. Join the world’s leading cord blood experts to learn about the latest cord blood and cord-tissue derived cell sources and their recent clinical uses in immunotherapy, gene therapy and regenerative medicine for sickle cell, GVHD, ARDS and viral diseases. The impact of COVID-19 on cord blood banking will also be addressed and current Cord Tissue MSC trials highlighted.
1. Understanding the strategies for manufacturing VSTs from cord blood
- Understand the advantages of CB VSTs over third party VSTs
- Obtain knowledge regarding the breadth of targetable viruses using CB as a donor source
- Review the complexities of manufacturing cord tissue MSCs.
- Present data using these cells in children with Autism Spectrum Disorder.
- Discuss novel applications for these cells in treating COVID-ARDS
- To understand the impact of the COVID pandemic on cord blood banks around the world
Co-Chairs: Patricia R M Rocco (BR) and Claudia Dos Santos (CA)
Mesenchymal stem/stromal cell (MSC) therapy holds promise for the treatment of acute and chronic lung diseases. The benefits of MSC-based therapies appeared to be induced by complex, well-orchestrated signaling pathways rather than by any one (or few) mechanisms. Safety results from phase I and II clinical trials are encouraging, but the safety and efficacy profile has yet to be proven in large-scale trials. In an ideal clinical scenario, MSCs would be promptly available and obtained through well-standardized procedures, but some barriers to the feasibility of MSC therapy still exist. In this symposium, we will discuss the current “state of the art” in success and failure of cell-therapy clinical trials for acute and chronic lung diseases. The ultimate goal is to establish an international framework for collaboration between clinical trialists, translational scientists, and the industry to serve as a platform for collaboration and advancement of clinical research in acute and chronic lung diseases.
Chair: Bill Milligan (CA/TW)
Today the first two autologous CAR T therapies are commercialized in multiple developed countries, through dozens of health care facilities, and many hundreds of patients are benefiting from treatment! Now “industrializing” CAR T therapy to gain world-wide, broad patient access to this new standard of care, means not only extensive scale-up of manufacturing capacity but also transforming hundreds of health care centers into CAR T competent treatment sites using either autologous or “off-the-shelf” allogeneic products in treating patients. What are some key considerations for how academia, industry and healthcare centers can meet this challenge? Today we’ll explore autologous, allogeneic, and healthcare center perspectives from four experts active in pursuing this CAR T industrialization vision.
Elizabeth Hexner (US)
- Challenges and advantages of both allogeneic and autologous products
- Recognize existing structures in centers with decades of cell therapy expertise
- Minimizing complexity when launching a new product
- Considerations for successful commercialization of autologous CAR—Ts
- Manufacturing Network strategy and Apheresis network
- Preparation of Supply Network during clinical development
- Challenges and Opportunities for autologous CAR-Ts
Suma Rao (US)
- Introduction to allogeneic process and comparison vs autologous
- Challenges in delivering robust control strategy due to:
- Complex and new raw materials
- Emerging technologies in manufacturing and detection
- Single sourced materials and equipment
- Challenges associated with product definition when the product is not an entity but a population and the use of Quality Target Product Profile as a tool to address challenges
- Pioneering a revolutionary approach using renewable master induced pluripotent stem cell (iPSC) lines generated from our proprietary iPSC platform to derive cell therapy product candidates that can be delivered off-the-shelf for the treatment of a large number of patients.
- Our cell therapy product candidate pipeline is comprised of immuno-oncology programs, including off-the-shelf NK- and T-cell product candidates derived from master iPSC lines
- Challenges in cell culture scale up for allogeneic cell therapies with iPSC technology
Chair: Julie Allickson (US)
The severe and incurable stages of Chronic Venous Insufficiency (CVI) currently affect at least 1.5M patients in the EU and North America alone, with an approximately 300,000 new patients diagnosed every year. The disease significantly impacts quality of life and puts numerous patients out of work or into disability programs. CVI is a major burden to patients, employers, and health care systems. VERIGRAFT estimates that its first product, the personalised tissue-engineered vein (P-TEV), has the potential to cure patients with severe CVI and enable them to return to a normal life.
VERIGRAFT is just about to initiate a unique clinical trial program where P-TEV will be used to treat CVI. We have received approval for the first trial by the European authorities and are preparing for a pre-IND meeting in the US. The trial in Europe will be first of its kind worldwide, and one of the first tissue-engineered products clinically tested in Europe. The presentation will describe the road from research and an unmet medical need to a market authorization for this novel ATMP. Personalization and tissue-engineering of some other organs will also be mentioned.
Key items of the presentation:
- Generation of personalized tissue-engineered transplants
- Use of regenerative medicine to address so far incurable diseases
- Organ transplantation without the severe risks of immunosuppression
- Industrialization of a tissue-engineered ATMP, from bench to bedside
Optimizing a product through process development is a natural step in translating the therapeutic to the clinic. While this is a critical milestone, many of the processes have not been optimized for larger-scale industrialization. This session will evaluate how industry innovators are implementing new processing platforms and strategies to position future products for sustainable industrialization.
We will discuss the challenges in translating academic and start-up companies to first in man and early phase clinical trials. In particular we will explore the experience of the Birmingham group in embedding a European academic spin-out into their GMP manufacturing facility and equipping the company to develop its own manufacturing expertise. Furthermore, we will discuss the outcomes of the Innovate UK funded Advanced Therapy Treatment Centres and how this initiative is improving the logistics of ATMP manufacture and distribution
Chair: Emily Hopewell (US)
Process Validation – it has to happen! Join us to hear regulatory perspectives and real-world examples of considerations specific to autologous products, including both cells and tissues. Are normal donor cells ok to use? What risks are associated with validating your process using cells or tissues from healthy donors?
Antonio Ruiz-Garcia (ES)
Process validation is the documented evidence that the manufacturing process can consistently produce a result within specific parameters, that in the particular case of ATMPs the aim is to demonstrate that the finished product characteristics are within a given range. The limited availability of the cells / tissues which is typical for most ATMPs requires the development of pragmatic approaches, that has some differences between autologous and allogeneic products.
Understand the general differences in the validation of the manufacturing process between autologous and allogeneic ATMPs, and how to plan such validation taking these differences into account.
Corey Smith (AU)
The presentation will discuss the approaches we have used At QIMR Berghofer to develop T cell immunotherapies to target viral infection in immunocompromised patients, cancer patients and patients with autoimmune disease. It will discuss some of the lessons we have learned from the transition from healthy donors for process optimization and validation to the use of patient material in manufacturing that may be shipped from around Australia or overseas.
Aisha Khan (US)
Process validation means a successful demonstration of manufacturing and quality consistency, and it is the action of providing that any process, procedure, method, or activity actually and consistently fulfill specific requirements. This session will outline the process validation steps by using examples of autologous and allogenic products.
- Understanding and using FDA’s Process Validation Guideline
- Is process validation for autologous is different than allogeneic?
- How to validate process for Investigational New Drug (IND) applications?
- Establishing and maintaining control of complex processes, as well as achieving regulatory approval of new products.
- Understanding the importance of process validation as a means of minimizing the concerns related to cell manufacturing.
- Monitoring, process changes and when to revalidate.
Recent advances in genome editing technologies have substantially improved our ability to make changes in the genomes of eukaryotic cells. Viral vectors and programmable nucleases are already revolutionizing our ability to interrogate the function of the genome. This session provides an overview of current progress in qualifying and regulating targeted genome editing technologies as they are being used clinically to correct or introduce genetic mutations to treat diseases that are refractory to traditional therapies. Preclinical assessment and GMP manufacturing of these technologies as well as the regulatory requirements for FIH clinical trials utilizing these technologies will be discussed.
Making changes to the manufacturing process/product is an inevitable part of process development with the goal of making a better product. There is a risk if manufacturing changes are made late in the clinical trials that they could potentially change the product’s critical characteristics
Foreign regulatory authorities as well as FDA have broadly adopted the requirements defined in ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process for establishing product comparability. The comparability study is defined as a prospective study protocol designed to demonstrate that two products are comparable before and after the change. In some cases, the Agency may ask the IND sponsor or applicant to submit the comparability study for assessment and review prior to the data collection and analysis.
In ICH Q5E comparability is defined as a conclusion that products are highly similar before and after manufacturing process changes with no predicted adverse impact on the quality, safety, or efficacy of the drug product. This conclusion is most often based on an analysis of product quality attributes. In some cases where subtle analytical changes are seen, nonclinical or even clinical/immunogenicity data might be indicated. When this document was written in the 1990’s, biological (biotech) products were within scope, unfortunately cell and gene therapy products were not because this product sector was in its infancy.
This session will focus on providing stake holders with some guidance about best practices to follow to demonstrate comparability and major consideration and essential element of well-designed and executed comparability studies.
Comparability studies of genetically modified autologous cell therapy products could be challenging in many aspects. Different approaches and limitations to each will be discussed.
Mohamed Heidaran (US)
Krishnendu Roy (US)
This talk will outline how multi-omics based big-data analytics and multivariate predictive modeling can be used to better understand cell manufacturing processes and develop putative CQAs, early predictive markers, and identify critical process parameters to enable product and process comparability and understand mechanism of actions.
Chair: Ivan Martin (CH) & Joan Garcia-Lopez (ES)
The field of regenerative medicine has shown tremendous growth in just a few short years, with advancements at all stages of translation for cell-based therapeutics. This session will highlight important considerations and recent steps taken to improve the safety and efficacy of regenerative medicine products as the CGT field continues to rapidly expand. Harmonization of terminology, labeling, and point of care manufacturing will be discussed followed by a look into the importance of registries and real-world data.
Christian Chabannon (FR)
The EBMT is devoted to the promotion of all knowledge associated with the transplantation of haematopoietic stem cells from all donor sources and donor types including basic and clinical research, education, standardization, quality control, and accreditation for transplant procedures.
Our mission is to save the lives of patients with blood cancers and other life-threatening diseases by advancing the fields of blood and marrow transplantation and cell therapy worldwide through science, education and patient care.
The Tissue Engineering and Regenerative Medicine International Society (TERMIS) aims at worldwide development and application of science and technologies in tissue engineering and regenerative medicine. To accomplish this purpose, TERMIS brings together an international and interdisciplinary community of persons engaged or interested in the field and promotes education and research through regular meetings, publications and other forms of communication. This symposium is co-organized with the European Chapter of the Society (TERMIS-EU).
Speakers will present their experience with imaging cellular therapeutics to bring awareness to how non-invasive in-vivo cell tracking technologies and methods can provide unique opportunities to optimize efficacy of cell-based therapies and aid in the assessment and management of eventual toxicities, and ultimately, benefit their clinical translation.
- To learn about the different imaging modalities for monitoring cellular therapies
- To learn about developing and available, clinically applicable cell tracking technologies
- To learn how imaging can aid in the translation of cellular therapeutics
HESI is an independent non-profit dedicated to bringing together global teams of scientists from academia, government, industry, and NGOs to solve the most pressing risk and safety challenges facing humans and the environment today. Our scientific program focus areas span from basic research and discovery to applied decision-frameworks. All of our initiatives provide fit for purpose science to address contemporary health and safety challenges. As a non-profit, charitable organization, HESI’s mission is to generate information and scientific resources of benefit to global public health. In support of this objective, all HESI projects make a contribution to the scientific public domain via publication in the peer-reviewed literature, deposition of data in publicly accessible databases, workshops and/or other public outreach efforts.
HESI committees generate impactful collaborative science via a variety of mechanisms, including designing and conducting novel laboratory research, pooling and analyzing existing data, creating decision frameworks and methodologies, and identifying scientific best practices. HESI is based in Washington D.C., USA, but operates globally.
HESI’s Cell Therapy – TRAcking, Circulation, & Safety (CT-TRACS) committee was launched in 2016 to identify key needs for assessing the safety of cell therapies and identify opportunities to meet these needs. This program provides a neutral platform for cell therapy developers, researchers, regulators, imaging specialists, CROs, enabling tools developers and other stakeholders to interact, discuss current challenges and identify best practices to ensure that these therapies are safe and effective for use. It brings together an international and multi-disciplinary team of experts with interest in sharing their knowledge, common challenges and seek consensus on finding harmonized solutions. In particular, the committee aims to bring awareness on how the application of existing cell tracking technologies, methods, and best practices can benefit the clinical translation of these new therapies.
Session Description Forthcoming
Scott Burger (US) – North America
Christopher Bravery (UK) – Europe
Janet Macpherson (AU) – Asia Pacific
Alex Nancekeivill, Chief Business Officer, Asymptote part of Cytiva, United Kingdom
Alex Guite, PhD, Vice President, Services and Alliances, World Courier, United Kingdom
Cytiva, formerly GE Healthcare Life Sciences, introduces the VIA Capsule, the first liquid nitrogen-free cryogenic shipment system, designed specifically for the transportation of cellular therapies.
- Recognize the challenges experienced with cell therapy logistics today
- Understand how the VIA Capsule system delivers a more controlled, assured and patient focused way of shipping cellular products
- Discover how the VIA Capsule reduces the complexity, risks and inefficiencies associated with current shipping methods
- See the benefit of shipping the VIA Capsule within the World Courier global GDP certified network
- Discover the global experience with the VIA Capsule
For more information talk with us at the Cytiva booth within the ISCT Exhibition Hall or visit Cytiva.com
Chairs: Lesley Eschinger (US), Peter Gee (JP)
Currently, the gold standard in the manufacturing of chimeric antigen receptor T-cells (CAR-T) is based on viral gene transfer. As this is associated with high costs and safety regulations, it has been critical to develop a new viral-free CAR-T manufacturing protocol. This session will focus on the manufacturing of CAR-T cells by both piggyBac and Sleeping Beauty (SB) transposon gene delivery systems using optimized electroporation protocols for clinical applications. The viral free manufacturing process is designed in such a way that permits scale-up and reduction in the regulatory burden associated with conventional viral gene-transfer. Using an optimized, up-scaled protocol allows for the production of a CAR-T product at a magnitude that will permit treatment of patients, while showing high viability as well as antigen dependent tumor recognition and elimination in vitro. Experiments to determine the anti-tumor potency of the drug product in vivo and detailed genomic analyses are ongoing.
Presenters: Ali Mohamed (USA), Félix A. Montero Julian (FRA), Dominic Wall (AUS)
The successful development and commercialization of Cell and Gene Therapy products opened a hope for patients with urgent medical needs and opened a door for a new era of modern medicine.
However, the manufacturing of C> products is very complex and they have to be released in a short timeframe. These are high value products, available in limited quantity that should be controlled employing complex set of tests in order to ensure identity, safety and potency.
The current microbiological compendial methods like sterility and mycoplasma testing are not adapted to these products. During this tutorial industry experts will address the QC Testing Strategies to Improve Manufacturing Turnaround Time, the bioMérieux Microbiology Testing Solutions to Increase Operational Efficiency and Improve Patient Safety and will discuss How to Make Rapid Testing Mainstream for ATMPs through a Question & Answer session.
Chair: Carson Rhodes (USA)
Speakers: Dalip Sethi (USA), Mark Jones (USA), Nathan Frank (USA)
• CD3+ T Cells: Clinical dose reached in 8-9 days, with consistent viability, fold expansion and doubling times
• Tregs: Increase Scale and Viability with Automation
• MSCs: Culture up to 1.9 Billion MSCs in 5 days using Rooster Bio MSCs and xeno-free medium.
Immunotherapy is changing the landscape of cancer treatment, but most available tools are adapted and not purpose-built for this cell-centric workflow. Agilent Technologies is dedicated to supporting these next-generation therapies, providing key technologies to measure immune cell function, enabling researchers to achieve the necessary level of therapeutic potency and safety.
Bill Milligan (CAN)
Cláudia Lobato Da Silva (PRT)
Large cell doses (>1×106 cells/kg) have been required for clinical implementation of MSC-based therapies and the success in obtaining those cell numbers starting from select human tissues is dependent on efficient ex-vivo expansion protocols able to comply with GMP. In past years, we have established scalable expansion of human MSC in bioreactors and have demonstrated potential to maximize cell productivity by changing several parameters, including the utilization of serum-/xenogeneic-free (S/XF) culture supplements, as well as different tissue sources, and bioreactor configurations. This talk will summarize methods and primary results for scalable hMSC expansion in three bioreactor systems using human Platelet Lysate (hPL) supplements (UltraGROTM brands):
1) Microcarrier-based spinner flask system for the expansion of umbilical cord (UC)-derived MSC.
2) Terumo’s hollow fiber Quantum Cell Expansion System for the expansion of adipose tissue (AT)-derived MSC.
3)Microcarrier-based PBS Vertical WheelTM Bioreactor for the expansion of both UC- and AT-derived MSC.
Our focus was to establish an integrated platform using hPL supplements capable of supporting efficient isolation (from primary tissue samples) and cost-effective expansion of hMSC for clinical development and commercial scale production.
Michael Kapinsky (GER)
While there is solid consensus on the crucial phenotypic features associated with multipotent human mesenchymal (Dominici et al. Cytotherapy 2006) and hematopoietic stem cells (Dmytrus et al. BM Transplant 2016; Cimato et al. 2019), substantial bias and lack of precision continue to concern flow cytometry users. A major portion of the variability observed can be contributed through sample preparation by human operators. The DURA Innovations dry reagent technology eliminates manual antibody pipetting, provides expert antibody panel design and assures lot-to-lot consistency, supporting the scientific rigor needed in clinical stem cell research.
Julie Smolich (USA)
The COVID-19 pandemic has brought new challenges to the already complex delivery of cell and gene therapies. Now, more than ever, it’s critical that your cell therapy supply chain is expertly designed, managed, and utilizes infrastructure that’s proven to deliver through even the most unprecedented times. Throughout the past 30+ years, our expertise and established relationships have successfully delivered 100,000+ time-sensitive cell therapies. In this presentation, you’ll receive expert insight from Be The Match BioTherapies about the systems, teams and infrastructure that’s critical to minimizing variability throughout the cell therapy supply chain and ensuring patients receive the therapy their life depends on.
Learn more: https://bethematchbiotherapies.com
Mira Genser-Nir (ISR)
hMSC are a critical raw material for cell-based therapies and usually a large number of cells are required for clinical applications.
Cryopreservation is currently the only method to preserve cells with maintained functional properties and genetic stability for long term storage.
To date, a common practice is use of homebrew cryo-medium that is composed of animal-derived raw materials and low Mw Cryoprotective agents (CPAs), usually 10-20% DMSO. Alternatively, animal component free (ACF) freezing solutions were developed for clinical applications, but they are still based on culture medium and are composed of 10% DMSO (e.g. NutriFreez™ D10). In addition, a few products were developed with a reduced concentration of DMSO or even without DMSO. However, these products appear not to be optimal for hMSC. Moreover, most of the commercially available DMSO-free products are actually composed of other potentially toxic permeable CPAs (e.g. Ethylene Glycol, EG). Exposure of cells to these materials can impact the quality, safety and efficacy of cell-based therapeutic product. Facing strict regulatory requirements, the development of defined, ACF, salt base freezing solution with reduced concentration of DMSO is essential.
The current study presents the feasibility of a novel defined, ACF, protein free, salt base freezing solution composed of 5% DMSO for cryopreservation of hMSC from various sources. Results show that the novel cryopreservation solution efficiently maintains high cell yield and viability and supports the recovery of hMSC while maintaining the normal hMSC features: typical fibroblast-like cell morphology, phenotypic surface marker profile, differentiation capability as well as self-renewal potential.
Clinically accepted, cryopreservation solution for hMSC holds a unique opportunity to facilitate the translation of these cells to cellular therapy applications.
With the alarming spread of SARS-CoV-2, several companies have started testing repurposed MSC-based therapies for Covid-19 patients suffering from acute respiratory distress (ARD). These efforts are partially supported by prior studies that evaluated MSCs in inflammatory lung diseases, and which produced compelling safety data, albeit providing no evidence for clinical efficacy. Caution is advised, therefore, against the use of repurposed treatments in Covid-19 patients, especially in light of recent data showing marginal benefits of repurposed drugs in an increasing number of patients, despite high initial expectations.
With this warning in mind and relying on years of MSC-related experience, in-house MSC manufacturing capacity, and the technologies, we developed, for the efficient and standardized isolation and cultivation of MSCs, Bonus Therapeutics has developed MesenCure, an enhanced allogeneic MSC-based product designed, explicitly, for treating ARD in Covid-19 patients.
Preclinical results show that MesenCure, enhanced by biological, chemical, and physical means, but not untreated MSCs, have managed to alleviate lung edema and reduce lymphocytes’ infiltration. These results imply that naïve MSCs, merely repurposed, might not be enough, as well as emphasize the prospects of MesenCure in Covid-19. Bonus Therapeutics is continuing the development of MesenCure and expects to enter clinical trials within six months.
This innovative solution to tests mycoplasma is a game changer, it allows a broad detection in one hour, is totally automated and really easy to use. This technology is based on a “lab in a pouch” disposable that contains all reagents and controls necessary for a rapid molecular test. Thanks to its automation from sample to result with 2 minutes of hands on time, and its low footprint, this solution can be used for at line testing outside of the context of a high level of expertise laboratory. This is the first method allowing at-line in-process controls, and rapid release of products in 1h.
Dominic Wall (AUS)
Gerry McKiernan (AUS)
Shae Disney (AUS)
Conducting the tech transfer of a commercial CAR-T product is a challenging proposition. There are many considerations that a manufacturing organization must undertake to successfully overcome these challenges. Our presentation will focus on the different aspects of a commercial CAR-T tech transfer – business, quality & regulatory, and clinical supply chain & logistics – that are critical to successful implementation.
Sebastian Warth (GER)
The manufacturing process of T cell products requires reagents that meet the regulatory guidelines and ensure cellular products of consistent quality. Many current manufacturing protocols rely on human serum-containing media. Human serum requires extensive testing prior to use for production of cellular products due to lot-to-lot inconsistencies. Moreover, human serum is a limited resource and might not be available in quantities needed for commercial manufacturing.
The CellGenix® T cell Medium (CellGenix® TCM) offers a ready-to use, serum-free and xeno-free alternative for rapid expansion of functional human T cells. Cultures in CellGenix® TCM exhibited high cell numbers early after activation and throughout culture with high cell viability.
T cells expanded in CellGenix® TCM acquired an early-differentiated phenotype and a high proportion of polyfunctional cells. CAR T cells generated with CellGenix® TCM achieved a high “specific killing” of target cells and demonstrate the functionality of the T cell product. High expansion and viability with CellGenix® TCM in a classic culture dish translate well to the G-Rex® culture device with enhanced gas exchange, which is widely used in clinical settings.
EFS is the only French National transfusion service. Moreover, EFS puts its experience in Research so as to facilitate access to new treatments, for cell and gene therapies.
EFS has become a key ATMP European player in the development and production of innovative therapies (CDMO) drugs.
EFS Pharmaceutical Establishment has 5 platforms, with 16 ATMP – Class B production rooms. EFS expertise covers a wide range of GMP services, from development up to clinical stages manufacturing, in the following areas:
- Immunotherapy (CAR-T Cells and Dendritic Cells)
- Regenerative Medicine (Mesenchymal Stem Cells – MSC, Differentiated Pluripotent Cells, iPS and hECS)
- Hematopoietic Stem Cells (CSH)
- Cell Bank Productions
EFS can support project owners (Academic, Biotech or Industrial) thru project diagnosis, process development, scale-up, GMP preclinical or clinical batches manufacturing, development and implementation of analytical tests (EP/ICH).
In addition, EFS can provide a strong support within a regulatory framework as well as a very helpful access to clinical staffs, promoting interface and advancement of clinical trials.
Some examples of successful collaborations: PDC Line Pharma /ADIPOA2 – European project H2020/ Clinical Trial Side by Cide/ Orthounion – Project H2020/ STREAM CECS ISTEM/ Protocol Excellent – Cellpothera.
Large cell numbers are needed for the development of cell therapies and stem cell-based drug research applications. By utilizing its strong synergies in cell culture expertise, bioreactor technology, and polymer manufacturing, Eppendorf has emerged as an expert partner for the cultivation of stem cells at large scale. With our equipment, training programs, and application services, we support scientists in resolving cultivation bottlenecks during the development of advanced stem cell-based applications. The need for advanced solutions is increasing. With our expertise, we help to stimulate the growth of your cultures and cultivate solutions tailored to your challenges.
Cell wash, concentration and final formulation in the cell therapy field remains a challenge. Once cells are harvested, time and technology suitability, are critical to ensure processing conditions will not affect cell viability and activity. With the application of acoustic wave separation techniques, which enables a lower shear separation method, these critical process steps have a new solution. In this presentation, we will review the evaluation of the FASTBox device, the precursor to the ekko™ acoustic cell processing system, at bluebird bio, for effective volume reduction and media replacement for a CAR-T drug product.
Haro Hartounian (USA)
There is a collaborative effort underway at the New Jersey Innovation Institute (NJII) to advance the biopharma industry. NJII is a non-profit owned by one of the top polytechnic universities in the United States and its Biopharma division and its advisors represent some of the most influential members of the industry.
NJII has the only facility designed to provide flexible process development and clinical manufacturing of cell and gene therapies located on a University campus in the United States. In addition the team is pioneering several efforts related to workforce development and the support of innovative biopharmaceutical companies focusing on cell and gene therapies.
Dr. Haro Hartounian, a 30 year expert and the general manager of the division, will lead this presentation describing the types of collaborative efforts and projects underway as well as the capabilities of BioCentriq, the division’s cell and gene therapy development center.
Gene therapy clinical trials often require high titer vector preparations to adequately deliver the therapeutic transgene, in great excess of research-level production utilized in many laboratories. Bioprocessing for the therapeutic agents for these therapies still face many challenges during scale up. Here, we will present a case study which illustrates the challenges and solutions to scale up process steps required to manufacture AAV9.
We evaluated AAV9 production in adherent HEK293 cells utilizing the small scale iCELLis Nano fixed-bed benchtop bioreactor. Based on conditions developed in the pilot iCELLis Nano bioreactor system, we scaled this production to the large scale iCELLis 500 bioreactor (200 m2 and 333 m2 surface area). A HEK293 cell seed train was utilized, using the Xpansion® 200 bioreactor to generate sufficient cell numbers for seeding the bioreactor. Transfection reagents were scaled for efficient transfections. Media components, such as glucose as well as O2 and CO2 were evaluated and replenished as needed throughout the run using the perfusion process of the iCELLis bioreactor. Following a production phase, >1016 vector genomes were isolated from crude harvest of the bioreactor.
Todd Sanderson (USA)
Recent advances in cell and gene therapies have opened the door to bringing life-saving, curative treatments to many patients and families. Many of these therapies rely on adeno-associated virus (AAV) or lentivirus (LV) viral vectors for gene transfer. Industrialization of these therapies requires robust, scalable manufacturing processes. Existing technologies can be readily adapted for viral vectors. Planar and fixed-bed adherent bioreactors are valuable tools in upstream vector production for both seed train biomass and vector production. Purification of these vectors can be achieved using scalable, single-use technologies including direct-flow filtration (depth and sterile), membrane-based ion exchange chromatography, and tangential-flow filtration (TFF). Here we present a strategy for utilizing these single-use technologies from Pall Biotech for both AAV and LV manufacturing platforms.
Breanna Borys (CAN)
Human induced pluripotent stem cells (hiPSCs) hold enormous promise in accelerating breakthroughs in understanding human development, drug screening, disease modeling and cell and gene therapies. Their potential, however, has been bottlenecked in a mostly laboratory setting due to bioprocess challenges in the scale-up of large quantities of high-quality cells for clinical and manufacturing purposes. While several studies have investigated the production of hiPSCs in bioreactors, the use of conventional horizontal-impeller, paddle and rocking-wave mixing mechanisms have demonstrated unfavourable hydrodynamic environments for hiPSC growth and quality maintenance. We developed a scalable, single-cell inoculation protocol which successfully maintained cell growth rates without sacrificing cell quality, and we have provided the first published protocol for in-vessel hiPSC aggregate harvesting, permitting the entire bioreactor volume to be dissociated into single-cells for serial passaging into larger scale reactors. Importantly, the cells harvested and re-inoculated into scaled-up vertical-wheel bioreactors not only maintained consistent growth kinetics, they maintained a normal karyotype and pluripotent characterization and function. We have demonstrated the success of these protocols in cultivating large quantities of hiPSC aggregates in vertical-wheel bioreactors using a wide variety of commercially available pluripotent stem cell media types.
In Cell and Gene therapy, the race is on to optimize manufacturing, advance technical capabilities and assemble the necessary teams to broaden application and impact. Philadelphia and Penn Medicine are leading national and global efforts in Cell and Gene Therapy and Connected Health — Welcome to Cellicon Valley.
The number of ATMP therapeutic-based medicines for inherited genetic disorders is in constant growth, with a global 32% increase in new clinical trials in the last 4 years. ATMPs have demonstrated their success with already more than ten approved for commercialization. The success of AAV as the most promising viral vector for gene therapy is due to low immunogenicity, broad tropism and non-integrating properties. One major challenge for translation of promising research to clinical development is the manufacture of sufficient quantities of AAV. Transient transfection of suspension cells is the most commonly used production platform, as it offers significant flexibility for cell and gene therapy development. However, this method shows some limitations in large scale bioreactors: inadequate transfection protocol, reduced transfection efficiency and lower productivity. To address this concern, we present data on the novel transfection reagent showing: i) increased AAV titers, ii) improved transfection protocol for large scale bioreactors and iii) reproducibility of viral titers at different production scale. The aforementioned optimized parameters make this novel transfection reagent ideal for cell and gene therapy developers by combining the flexibility of transient transfection with scalability and speed to market.
Human Mesenchymal Stem/Stromal Cells (hMSCs) are critical raw materials in numerous therapeutic approaches including cell therapies, cell-based gene therapies, tissue and organ engineering, medical devices and exosome and extracellular vesicle-based therapies. RoosterBio, Inc. is a privately held cell manufacturing platform technology company focused on accelerating the development of a sustainable Regenerative Medicine industry, one customer at a time. RoosterBio’s high-volume, cost-effective and well-characterized adult hMSCs paired with highly engineered bioprocess media systems are built for rapid manufacturing scale-up, thus removing several years and millions of dollars from product development and clinical testing. This approach revolutionizes how regenerative medicine products are developed, clinically translated, and commercialized. In response to the current COVID-19 pandemic, our scalable hMSC manufacturing systems could address therapeutic needs for a huge demand of clinical grade hMSCs and hMSC-derived products. The newly launched product RoosterCollect™-EV-CC is the world’s first cGMP extracellular vesicle collection medium. This product is a key addition to RoosterBio’s cGMP solutions.