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PROGRAM CHAIRS:
Martin A. Giedlin, PhD - Poseida Therapeutics, Inc.
Gary K. Lee, PhD - Sangamo Therapeutics, Inc.


Joseph M. Roig
Sr. Scientific and Medical Liaison, Terumo BCT
The Role of Leukapheresis and Elutriation in Cell Immunotherapy Manufacturing

Abstract

There is plenty of literature about the manufacturing process of the different types of cell immunotherapy products, yet the first step in this process is more often than not described with one single word: leukapheresis. The purpose of this presentation is to describe the apheresis technology used to collect the peripheral blood cells (lymphocytes, monocytes, and/or PBPC [CD34+]) later used as a raw material for the cell immunotherapy manufacturing process, as well as how potential issues like patient’s characteristics can be managed to optimize the collection process and minimize the variability of the collected products. The last, but not the least, enrichment of white blood cell subpopulations through another physical separation method called elutriation, aka counter-flow centrifugation, will also be described.

Biography

Joseph Roig, whose background is Science of Chemistry (BS, 1980, University of Barcelona) as well as Transfusion Medicine and Cell Therapies (MSc, European Master in Transfusion Medicine and Advanced Cell Therapies [EMTACT], 2016, European Consortium of Universities), has been working in the field of physical technology of blood cell separation since 1991, the year he joined COBE BCT, nowadays Terumo BCT. He is currently working in the Medical Affairs department and his specialty is the optimization of blood cell collections.

Dan Kopec
Technology Expert Process Analytical Technology, Sartorius Stedim Biotech
Integrated, Closed System PAT Analytics for Advanced Auto Feedback Control
of Critical Process Parameters – Reactive Analytics

Abstract

New product modalities and market dynamics, along with strict manufacturing requirements, drive the ongoing need for significant improvements in bioprocessing. Specifically, the need to apply automation/feedback control to mitigate risk and improve process efficiencies. This is especially true for the cell therapy manufacturing process, cell expansion phase. The stakes are now higher than before, given the autologous/unique nature of the product, the limited material, and tighter timelines. If we were to apply classic bioprocess control to this process with highly variable starting material, meaning: using fixed or static process conditions with data limited offline sampling, we will either 1) be operating in a very wide design space where we cannot truly meet our desired efficiencies, or 2) not running a very robust process – one that would surely be prone to failure. The good news is that there are now modern and systems integrated, advanced analytical tools which can provide robust and real time feedback in a closed monitoring bioreactor system. With these new tools, we can achieve a much safer, more efficient, and risk averse process when we utilize this real-time data in a feedback loop to automatically control our critical process parameters (CPPs) within a tighter design space; and do this with as little human intervention as possible. This talk will highlight new, pre-sterilized/in-situ PAT technologies for advanced process control in single-use bioreactors (rocking motion/wave and stirred tank format) for fully automated feed and bleed control via real-time monitoring of nutrients and viable cell volume.

Biography

Dan Kopec is a PAT Technology Expert for Sartorius Stedim Biotech in North America. Dan has over 15 years with Sartorius Stedim and 20+ years’ experience in process sensors for monitoring, control, and automation in biopharma, food, and chemical industries.

Kendra Hightower, PhD
Senior Study Director, Metabolon, Inc.
Metabolomics: Enabling Understanding and Optimization
of Bioprocesses and Immunotherapies

Abstract

The output of a cell culture system is directly linked to metabolism, the active biological processes in the cells. Gaining insight into active biology and the inputs that affect active biology is critical for optimal cell culture performance. There is increasing awareness that metabolism is a key functional driver for immune cell activation, growth, and differentiation and that understanding the fundamental role of active biology in immunometabolism is important for development and optimization of immunotherapies. Metabolomics provides unique biological insight into cellular processes and is an ideal tool for assessing active biology. By presenting a comprehensive biochemical view of the cell culture system, metabolomics enables the interrogation of genetic, environmental, and process design factors that affect cellular metabolism, influence the production process, and impact product yield and quality. We will describe how metabolomics can be applied to enable understanding of bioprocesses and immunotherapies and to expand the opportunities for process characterization and optimization.

Biography

Kendra Hightower is a Senior Study Director at Metabolon where she is engaged in enabling and interpreting metabolomics studies that address scientific questions across the research, development, bioprocessing, and consumer goods space. Over the past 30 years she has established a broad foundation in the biological and chemical sciences with experience in pharmaceutical, academic, and government R&D and pharmaceutical manufacturing. Before joining Metabolon Kendra spent 14 years in pharmaceutical R&D and biological manufacturing where she contributed to and provided leadership for drug discovery, drug development, post-marketing surveillance, bulk bioprocessing, and vaccine fill/finish efforts. Kendra received a BS in Biochemistry from the University of Maryland, College Park, and a PhD in Biology from Johns Hopkins University.

Jessie H.T. Ni, PhD
Chief Scientific Officer, Irvine Scientific
Chemically-Defined Culture Media for Advancing Cell Therapy Technology

Abstract

Cell-based immunotherapy applications are widely captivating today due to their clinical potential to become life-saving therapies for cancer patients. Generation of sufficient, desired cell populations is an essential task for the successful development of cell-based immunotherapies, which require an effective, scalable, and consistent ex vivo process. A suitable chemically-defined (CD), animal-component-free (ACF) cells basal media for major immune cells, such as T-cells and natural killer (NK) cells, would significantly foster the establishment of such a process. By applying spent media analysis and the quality by design (QbD) approach, we examined the effects of various key media compositions such as amino acids, vitamins, minerals, and lipids on activated human peripheral blood-derived T-cells or NK cells expansion. The results from our studies were used to develop CD, ACF basal expansion media for desired T-cell and NK cell populations, including NK-92 cells that are comparable to media containing serum, and further indicate the need to develop cells- and application-specific basal media to establish an optimal production process for a desired/targeted immune cell-based therapy under CD conditions. How an optimal ACF, CD culture process at scale can be achieved when switching from a serum or serum-derived component-containing process will be demonstrated using the case study of T-cell culture.

Biography

Jessie Ni received her PhD in Molecular Biology and postdoctoral training in Immunology from the University of Minnesota. She also has a Master's in Management of Technology from Carlson School of Management, University of Minnesota. Jessie has expertise and a track record in developing and commercializing reagents for life science applications. Before joining Irvine Scientific, Jessie spent more than ten years at R&D Systems directing and managing the development and manufacturing of recombinant proteins, antibodies, and cell culture media which helped to advance cell therapy research and applications. Since joining Irvine Scientific in 2012, Jessie has led the R&D team to develop much improved animal component-free and chemically-defined culture media for major primary cells and cell lines for their applications in cell therapy, assisted reproductive technology, and industrial bioproduction.

Chia-Hsing Pi
PhD Candidate, University of Minnesota
Chemically-Defined Culture Media for Advancing Cell Therapy Technology

Abstract

Both mixed and highly purified subsets of T-cells are being used therapeutically, and recent clinical trials have demonstrated clinical efficacy of these therapies. Current methods of preserving lymphocytes using 10% vol/vol of dimethyl sulfoxide (DMSO) and a cooling rate of 1°C/min are inadequate. Post-thaw recovery of T-cells (CD3+ cells) in apheresis products was significantly lower than other cell types present. Cryopreservation also influences post-thaw function. Cryopreservation has been shown to reduce levels of intracellular ATP, as well as antigen and cytokine expression in T-cells. Studies in our laboratory have developed novel methods of preserving T-cells using non-toxic, naturally occurring molecules. Other considerations with the preservation of T-cells include quality of the cells immediately prior to cryopreservation, factors that influence post-thaw function, and consistency of outcome. The long-term goal is to improve preservation of T-cells.

Biography

Chia-Hsing Pi is a PhD candidate in Mechanical Engineering from the University of Minnesota - Twin Cities. He also received a Master's of Science in Engineering degree in the Department of Mechanical Engineering and Applied Mechanics at the University of Pennsylvania. His wide research background includes mechatronics, semiconductor fabrication, micro/nano devices, and biomedical engineering. His current research field is biopreservation and cryoengineering, especially in the applications of cellular therapies.

David L. Hermanson
Vice President, Preclinical Development, Poseida Therapeutics, Inc.
CAR T-Cells with Non-Viral Gene-Editing Technology

Abstract

Autologous CAR T-cell therapies are individualized therapies that must be manufactured separately for each patient. Manufacture of these therapies is expensive and is viewed by some as a hurdle in their widespread adoption. Our non-viral gene-engineering system, known as piggyBac™, not only significantly reduces the cost of goods in manufacturing, but also improves the efficacy and safety of the final product. By utilizing only plasmid DNA and mRNA, the time and cost to make cGMP material required for manufacture is greatly reduced compared with viral-based systems. The very large cargo capacity of piggyBac allows for the incorporation of the CAR molecule, a safety switch, and a selection gene used to create a pure population of CAR-positive cells. Finally, the use of piggyBac transposition coupled with ex vivo expansion yields primarily a T stem cell memory (Tscm) phenotype that resulted in long-term persistence and durability of response in mouse xenograft models. Currently, a multi-center Phase I clinical trial is underway with a CAR-Tscm-based therapeutic for multiple myeloma.

Biography

Autologous CAR T-cell therapies are individualized therapies that must be manufactured separately for each patient. Manufacture of these therapies is expensive and is viewed by some as a hurdle in their widespread adoption. Our non-viral gene-engineering system, known as piggyBac™, not only significantly reduces the cost of goods in manufacturing, but also improves the efficacy and safety of the final product. By utilizing only plasmid DNA and mRNA, the time and cost to make cGMP material required for manufacture is greatly reduced compared with viral-based systems. The very large cargo capacity of piggyBac allows for the incorporation of the CAR molecule, a safety switch, and a selection gene used to create a pure population of CAR-positive cells. Finally, the use of piggyBac transposition coupled with ex vivo expansion yields primarily a T stem cell memory (Tscm) phenotype that resulted in long-term persistence and durability of response in mouse xenograft models. Currently, a multi-center Phase I clinical trial is underway with a CAR-Tscm-based therapeutic for multiple myeloma.

Bahram "Bob" Valamehr, PhD
Vice President, Cancer Immunotherapy and Reprogramming Biology
Fate Therapeutics, Inc.
Engineered Pluripotent Cell-Derived NK Cells as a
Cornerstone Approach for Off-the-Shelf Cancer Immunotherapy

Abstract

Natural killer (NK) cells represent a lineage of immune cells capable of direct cytotoxicity against tumor cells and are a critical source of key inflammatory cytokines. NK cell function is often impaired in the setting of cancer, reducing the effectiveness of the endogenous immune system. Pluripotent stem cell technology represents a unique and powerful approach to make cell-based immunotherapies available to a wide range of patients through the generation of a consistent and renewable “off-the-shelf” source of therapeutic cells. I will discuss our progress towards translating a unique and effective strategy to create a renewable source of “off-the-shelf” NK cells derived from a genetically engineered and single-cell derived master pluripotent cell line. Analogous to biopharmaceutical drug product development, the derived master pluripotent cell line is banked, characterized and repeatedly applied to our stage-specific directed differentiation process to reproducibly and reliably generate NK cells. The preclinical data highlight the therapeutic value of pluripotent-derived NK cells including augmented anti-tumor capacity, manufacturing reliability, and product safety. In summary, our pluripotent cell platform facilitates the development of “off-the-shelf” NK cell-based immunotherapeutics.

Biography

Bob Valamehr is the Vice President of Cancer Immunotherapy at Fate Therapeutics, overseeing the company’s immuno-oncology and pluripotent stem cell programs, including efforts to develop novel pluripotent cell strategies to create “off-the-shelf” cell-based cancer immunotherapeutics. Previously, Dr. Valamehr has played key scientific roles at Amgen, the Center for Cell Control (an NIH Nanomedicine Development Center), and the Broad Stem Cell Research Center developing novel methods to control pluripotency, to modulate stem cell fate including hematopoiesis, and to better understand cellular signaling pathways associated with cancer. He has co-authored numerous studies and patents related to stem cell biology, oncology, and materials science. Dr. Valamehr received his PhD from the Department of Molecular and Medical Pharmacology at the University of California, Los Angeles (UCLA) and his MBA from Pepperdine University.

Sean H. Kevlahan, PhD
Chief Executive Officer, Quad Technologies
T-Cell Activation Co-Stimulatory Ligands on a
Dissolvable Substrate to Modulate T-Cell Output

Abstract

Clinical and commercial potential for adoptive T-cell therapies (ACT) continues to grow rapidly. However, concerns around scalability, reproducibility, and costs are leading to an increased focus on improving biomanufacturing unit operation efficiencies and controls. T-cell activation represents one such critical unit operation, integral to the development and manufacturing of chimeric antigen receptor (CAR) or T-cell receptor (TCR) therapies. Product and process attributes are assessed via three general metrics: T-cell expansion, efficiency of genetic transduction, and phenotype(s) of the cellular product; the goal being to manufacture the maximum number of clinically beneficial cells in the shortest possible time. While commercially available T-cell activation products are able to activate and expand T-cells robustly, these products were not designed to elicit specific T-cell phenotypes or optimize transduction efficiencies. Thus, a demand exists for novel technologies with the potential to maximize expansion of transduced cells with clinically desirable phenotypes, and thus compress biomanufacturing workflows and reduce process costs. Transduction efficiency dictates how much viral vector is consumed in the process and the amount of transduced cells produced. Together these factors significantly influence overall cost of goods for the therapeutic product. Specific T-cell phenotypes are increasingly being associated with therapeutic benefits, driving both efficacy and persistence of the therapeutic product, which in turn are interconnected with dose and required scale of manufacturing. Given that bio manufacturing unit operations dictate both the performance and the cost of the therapeutic product, and the widespread desire of end users for innovation in this space, our thesis has been to expand the pallet of T-cell activation materials available to cell therapy developers by looking outside of conventional materials, workflows, and ligands for T-cell activation ligands.

In this presentation, we will describe development and characterization of a series of modified T-cell activation reagents built upon a novel biomaterials platform, ionotropic copolymer hydrogel microspheres which rapidly depolymerize and enter liquid phase upon application of low concentrations of a chelating agent. This platform enables us to vary the ratios, type, and density of co-stimulatory molecules presented to T-cells, and to remove the activation reagent during routine formulation washes with no additional debeading workflow steps required. We will demonstrate varying activation signals, phenotypes, and ratios of CD4/CD8 T-cells as a function of the aforementioned variables.

Biography

Sean Kevlahan is a product-driven entrepreneur, specialist in cell biology, and domain leader in cell/gene therapy bioprocessing where he is currently the CEO and co-founder of Quad Technologies. Dr. Kevlahan has received numerous awards including being one of the top-26 finalists in MassChallenge and a winner of the CASIS sidecar award. He is a lead inventor of many patents and has authored numerous publications utilizing Quad’s core Quickgel technology. Dr. Kevlahan holds a BS in biochemistry from Hofstra University and received his PhD in chemical engineering from Northeastern University.

At Quad Technologies, our mantra is to produce un-altered, viable, and pure cells with our products. We have developed a novel chemistry called Quickgel to which we can capture and release cells viably off of a variety of different substrates. We are actively pursuing the cellular immunotherapy workflow with our Quickgel technology by enrichment of T-cells, subsequent T-cell activation, and immediate decoupling of the cells from a substrate. We believe that by providing a facile release mechanism for cells, the end user could save a significant amount of manufacturing time, decrease COGS of their workflow, and produce better bioprocesses, and in turn better therapies.

Kimberly Lounds-Foster
Corporate Vice President, Global Supply, Celgene Corporation
Optimizing the CAR T-Cell Supply Chain

Abstract

The challenges of scaling a global autologous therapy supply chain are being solved with the initial commercial approvals of CAR T-cell products in the US. Having centralized manufacturing is the initial approach from most of the players in the space which presents several supply chain challenges:
• Optimizing global apheresis operations within a multi-purpose footprint
• De-risking the logistics between the nodes from vein-to-vein
• Defining make versus buy strategy to quickly set up clinical trials and ultimately a commercial footprint
• Ensuring integrity of chain-of-identify (COI) through the supply chain
• Ensuring supply continuity of critical raw materials in the manufacturing process

It is evident how the design of the clinical supply chain has had a high influence on the commercial supply chain. As more CAR T-cell products get approved, there is room to optimize the supply chain.

Biography

Kimberly Lounds Foster is Corporate Vice President of Global Commercial Supply and is leading the integrated plan, make, source, and deliver operations functions for all of Celgene’s commercial therapies. Kimberly’s team is responsible for designing and implementing the CAR T-cell commercial supply chain across Celgene’s autologous assets. Kimberly holds an MBA from The Wharton School, University of Pennsylvania and a BS in Chemical Engineering from Northwestern University. Kimberly is married and lives in Morris Plains, New Jersey.

Adria Carbo, PhD
Associate Director, Business Development, Therapeutics
Adaptive Biotechnologies
High Throughput Identification of Naturally-Occurring T-Cell Receptors with
Therapeutic Potential Against Tumor-Associated, Viral, and Neoantigens

Abstract

The growing use of immunotherapy to treat advanced cancers has brought about a revolution in techniques to mobilize the immune system to anti-tumor effect. Chimeric antigen receptor (CAR) T-cells targeting CD19 constitute the first modified T-cell products to garner FDA approval for clinical use. However, CAR technologies can only target cell surface antigens, representing approximately one quarter of potential targets. In contrast, T-cell receptor (TCR) therapies can target peptides presented by the major histocompatibility complex (MHC), including those derived from intracellular antigens. Hitherto, such receptors have generally been identified through low-throughput techniques using cancer patients’ blood, followed by affinity-maturation of TCRs, a step that can decrease safety. Here, we demonstrate a novel pipeline for the identification of potential therapeutic TCRs from the naïve repertoire of healthy individuals. Using a technique called multiplexed identification of T-cell receptor antigen (MIRA) specificity, we input hundreds of antigens of interest, including tumor-associated antigens, viral antigens, and neoantigens, and identify thousands of TCRs to these antigens. These TCRs then undergo evaluation for affinity, avidity, cytokine release, cytotoxicity, and safety. Cytotoxicity is demonstrated using both peptide-loaded and endogenously presented peptides. Safety is evaluated using alanine-glycine scans; evaluation of reactivity of TCRs against cell lines and primary cells is planned. We have fully characterized several TCRs targeting WT-1 which demonstrated improved avidity and cytolysis relative to a benchmark WT-1-targeting TCR, and a promising preliminary safety profile. We also show data for TCRs against shared neoantigens from PIK3CA, CDKN2A and PTEN.

Biography

Adria Carbo is an Associate Director at Adaptive Biotechnologies Corp. working with the cellular immunology TCR Discovery and the Business Development teams. Adria works towards advancing opportunities to develop and optimize the end-to-end discovery platform that generates potent, ultra-low frequency T-cell receptors (TCRs) with therapeutic potential. Adria has more than eight years of experience in developing new therapeutics in the field of Immunology. Prior to joining Adaptive in 2016, Adria transitioned into business development after working as a Scientific Director for Biotherapeutics Inc. (now spun-off to Landos Biosciences), a biotech company developing first-in-class molecules for T-cell driven autoimmune diseases. Adria has a PhD in Immunology from Virginia Tech.

John T. Elliott
Cell Systems Science Group Leader, National Institute of Standards & Technology
Achieving High Quality Cell-Based Measurement:
Application to Process Controls and Potency Assays

Abstract

Cell-based measurements are critical for process controls and potency assay used to manufacture cellular therapies. The application of measurement science concepts including identification of the sources of variability and strategies to monitor and control variability can be used to improve assay quality leading to confidence in measurement results. In this presentation, several examples of measurement infrastructure to enable high quality cell-based assays are described.

Biography

Dr. Elliott is the group leader of the Cell Systems Science Group under the Materials Measurement Laboratory at NIST. His current interest is the use of high quality characterization tools to describe cellular populations and the identification of non-destructive and other measurement techniques to monitor cell culture and treatments. He has interest in using measurement science tools to improve the quality of cell-based assays and is currently applying these tools to both cell-imaging and flow cytometry measurements. He received his PhD in Physiology and Biophysics from the State University of New York (SUNY) at Stony Brook.

Avery D. Posey Jr., PhD
Associate Laboratory Director, University of Pennsylvania
Enhancing CAR T-Cell Specificity for Malignancy and
Maintaining Durable Persistence in Solid Tumor Models

Abstract

Chimeric antigen receptors are engineered T-cell receptors with antibody-driven specificities that have so far been employed to break central tolerance and target self. For instance, redirection of T-cells to the pan-B cell marker CD19 has led to dramatic cancer remissions and sustained B cell aplasia in pediatric and adult leukemia patients, with persistence of CAR T-cells demonstrating the best correlation with durable response and remission. Redirection strategies for solid tumors have targeted tumor-associated antigens (TAAs), including Her-2/neu, mesothelin, and CEA, but anti-tumor efficacy has been underwhelming and severe toxicities associated with normal tissue damage have been observed. Most TAAs are often overexpressed in tumors but not exclusive to cancer and CAR T-cells with specificity for TAAs that can be indiscriminate for normal or malignant tissue. However, cancer-specific glycosylation, particularly the aberrant Tn or sTn O-linked glycans, are found at the plasma membrane in >80% of the most lethal cancers (lung, prostate, breast, colon, ovary, pancreas) and only as glycosylation intermediates within the golgi of normal tissue. These hypoglycosylated cancer glycoantigens decrease cell-cell interactions, increase the mobility and metastatic potential of tumor cells, and are associated with poor prognosis. Therefore, safer, cancer-specific CAR T-cells targeting glycosylated antigens are valid approaches for solid tumor therapy. Additionally, the signaling components of CAR T-cells influence the functions of these cells in vitro and in vivo, including cytokine secretion, proliferation, and persistence. We demonstrate that modifications to conventional CAR T-cell signaling can improve anti-tumor efficacy and persistence in solid tumor models. Combined, these results demonstrate a strategy for the development of safe, yet potent cancer-specific immunotherapies for treating most epithelial malignancies.

Biography

Avery D. Posey, Jr., PhD is an Instructor in the Department of Pathology and Laboratory Medicine; a member of the Parker Institute for Cancer Immunotherapies; Director of the Posey Laboratory within the Center for Cellular Immunotherapies at the Perelman School of Medicine, University of Pennsylvania; and an Assistant Professor at the Philadelphia Veterans Administration Medical Center. Dr. Posey holds a PhD in Genetics from the University of Chicago, a BS in Biochemistry from the University of Maryland, Baltimore County (UMBC), and a second BS in Bioinformatics from UMBC. Dr. Posey completed postdoctoral training in the laboratory of Carl June, where he generated glycosylation-specific chimeric antigen receptors to precisely target tumor-glycoforms of MUC1. The Posey Laboratory focuses on the development of novel cancer therapies for humans and dogs that genetically alter cancer patients’ own T-cells to improve the ability of the immune system to fight cancer. This research involves antigen discovery to identify tumor-specific targets, engineering strategies to surmount the tumor microenvironment, and altering the signaling and metabolic influences of T-cells to develop robust anti-tumor efficacy.

Cenk Sumen, PhD
Senior Manager, Business Development
Hitachi Chemical Advanced Therapeutics Solutions, LLC
Successful Manufacturing of T-Cell Therapies: Challenges and Opportunities

Abstract

The recent approvals of Kymriah and Yescarta has propelled us into the era of T-cell therapies, and these historic successes are just the beginning of what’s on the horizon. Despite the excitement of enabling the delivery of these life-saving therapies to patients, many manufacturing challenges remain for us to overcome. From the contract development and manufacturing organization (CDMO) perspective, a global outlook and the pursuit of standardization are key considerations which can enable cost-effective manufacturing for many different T-cell therapies across different geographies and supply chains. Automation and closed systems can reduce risk and provide a path forward in this regard, but many of these therapies remain in early clinical development, hence flexibility and adaptability also need to be considered across broad platforms.

Biography

Cenk Sumen, PhD is Senior Manager, Business Development at PCT, a Caladrius company. PCT is an industry leader in contract development and manufacture of cell therapy products. Cenk is tasked with business development, technology assessment, customer relationship management, and various sales and marketing functions for PCT. He is also an Adjunct Professor at NYU Tandon School of Engineering, Polytechnic Institute. Most recently, Cenk was Business Development Manager at PerkinElmer where he supported PerkinElmer's Drug Discovery Services business. Other prior positions included Technical Sales Specialist at STEMCELL Technologies, where he provided technical consultative sales for stem cell culture and differentiation systems, and Technical Consultant, Sales & Marketing at Life Technologies, where he served as scientific, strategic, sales, and marketing consultant for the Dynabeads technology platform based in Norway. He was also a Cancer Research Institute Fellow at Memorial Sloan-Kettering Cancer Center for two years.

Lisa Stehno-Bittel, PhD
President and Founder, Likarda, LLC
Cell Therapy: Islet Isolation and Transplant Quality Control Release Considerations

Abstract

Cell therapies are the basis for the exciting and quickly growing field of regenerative medicine, which holds great promise for cures from chronic diseases rather than continual palliative care, thus reducing total healthcare costs. Yet moving from a drug-based manufacturing process to cells as therapy presents many challenges. Early adopters of cell therapies often use an on-site, also called near-patient, manufacturing model. In this model, the cell donor is located near the recipient patient and all quality testing and preparation of the cells is conducted on site. While this model works well on a small scale, it is difficult and expensive for each clinical center to have their own GMP manufacturing facilities for full-process validation and workflow establishment. In a centralized manufacturing process, cells either from donors or from cell culture banks are processed at one site and shipped to the end-user. In centralized manufacturing, the starting cells must undergo quality testing, then they are typically processed in some manner, such as genetic manipulation or encapsulation, and eventually undergo release testing prior to shipping to the end-user, often a physician or veterinarian. In the first step, critical quality analysis (CQA) must be completed. This often includes assessment of specific proteins, mRNA, metabolic activity, secreted factors, and physical characteristics. These assays can be different from release testing procedures.

Our own research is focused on commercialization of islet transplants to treat diabetes, with a subsequent stem cell-derived cell therapy. For human clinics conducting islet transplants, a near-patient manufacturing model is often followed. In converting the standard quality control tests to our centralized manufacturing model, extensive research had to be conducted. We started with the common QC procedures used in the clinical sites, and adapted and tested them for centralized manufacturing. Some of the common quantitative and qualitative QC assays used for human islet transplants we have tested include islet equivalent (IEQ) determination, purity, viability, insulin release, and islet metabolic activities. We discovered that only one of the common QC tests, the total volume of cells, was reliably predictive of transplant success in our animal models. Tissue purity and viability were valuable in setting QC standards. In contrast, the popular functional assay of insulin secretion was not predictive of transplant success. New assessments that we are developing, based on academic research, include metabolic health and cell counts. In release testing, we must modify all assays because at that point our cells are encapsulated in a hydrogel. For example, standard viability assays could not be routinely applied to the encapsulated product. This presentation will review the approach taken to convert an on-site manufacturing procedure to a centralized model with emphasis on critical quality analysis and release testing.

Biography

With more than 25 years of academic research experience in the fields of cell biology and diabetes, Lisa Stehno-Bittel has over 65 publications. In 2012 she licensed her patents from the university and founded the biotech firm, Likarda. That year during Global Entrepreneurship Week, Likarda was named one of the 50 most promising start-ups in the world. As President, she guided the company to a revenue-positive status within 18 months of launching. Likarda conducts contract research for small start-ups as well as large pharmaceutical companies. Revenues raised by the service arm of the company support development of novel research tools and cell therapies aimed at diabetic companion animals. Dr. Stehno-Bittel still holds a part-time professorship at the university.

Xiaobin "Victor" Lu, PhD
Product Reviewer, Gene Therapy Branch,
Division of Cellular and Gene Therapies, OCTGT, FDA CBER
Regulatory Approval of Modern Gene-Based Cancer Immunotherapies —
CAR T-Cells — A Product Perspective

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a genetically modified cellular immunotherapy and holds considerable promise for cancer therapy, as evidenced by the recent Food and Drug Administration (FDA) approval of two CAR T-cell products targeting CD19 for treatment of B cell malignancies. Great interest and efforts are being generated in developing CAR T-cell products and moving them from research proof-of-concepts through clinical trials, and toward commercialization. However, many challenges in the development process and the potential to cause life-threatening toxicities remain to be fully addressed.

In this presentation, Dr. Lu will introduce the CAR T-cell immunotherapy concept and provide an overview of the CAR T-cell product manufacturing process. Dr. Lu will also discuss how the FDA manages the review process for a biologics licensure application (BLA) approval for a CAR T-cell product based on the current US FDA regulations. The focus of the presentation will be on chemistry, manufacturing, and controls (CMC) for a CAR T-cell product manufacturing process.

Biography

Dr. Xiaobin “Victor” Lu received his Bachelor’s degree in Biochemistry from Fudan University in Shanghai, China and his PhD in molecular virology from State University of New York (SUNY) at Buffalo. His PhD thesis work was focused on HIV molecular biology related to mechanisms of HIV-1 Rev and Tat regulation of post-transcriptional RNA processing. He was a postdoctoral fellow at the University of California, San Francisco (UCSF) where he studied HIV transcriptional regulation and HIV-1 Nef protein and Nef associated proteins. He worked at ONYX Pharmaceuticals as a research scientist and continued work on HIV-Nef-associated kinases. At VIRxSYS Corporation, he served as a senior scientist and later as a senior director for development of HIV and SIV-based lentiviral vectors for clinical studies. He played an important role in the development of the first HIV-1 based lentiviral vector for human clinical studies for HIV infected individuals. Later, he served as a senior scientific liaison at United States Pharmacopeia in charge of the Vaccines and Virology expert committee. Currently Dr. Lu is a product reviewer in the Office of Tissues and Advanced Therapies in the Center for Biologics Evaluation and Research (CBER) at the US FDA.

Sunetra Biswas, PhD
Senior Scientist, Analytical Development Product Sciences
Kite, A Gilead Company
Analytical Considerations Associated With the Development of Novel Modalities

Abstract

One of the biggest challenges for analytical scientists in the biopharma industry is the characterization of novel or complex molecules. While the analytical and structural characterization of monoclonal antibodies has become platformized, new and unique molecules such as cellular therapy products pose significant time and resource challenges for analytical scientists. YESCARTA is an approved autologous CAR T-cell therapy product that has ushered in a new era of patient-specific therapies. Due to the large heterogeneity of incoming patient material, robust analytical strategies are required for process and product control of new cellular therapy programs. In addition, comprehensive analytical characterization is key to understand, identify, and develop the appropriate quality control strategy for various phases of clinical development through commercial. This presentation describes analytical development and lifecycle management at Kite for comprehensive product understanding of our cellular therapy programs.

Biography

Sunetra Biswas, PhD is Senior Scientist, Analytical Development at Kite, A Gilead Company, in Santa Monica, California. Since joining Kite, Sunetra has developed analytical release assays across multiple technology platforms for Phase I and commercial products. Sunetra is responsible for Analytical Methods and Technologies Life Cycle Management strategy that includes method optimization, technology transfer, and performance monitoring. Sunetra leads a characterization group to develop assays to evaluate the vector and critical assay reagents. Sunetra received her PhD in Biochemistry, Cellular, and Molecular Biology from The Johns Hopkins School of Medicine, and postdoctoral training in Molecular Medicine from the Beckman Research Institute at City of Hope.

Linda L. Kelley, PhD
Senior Member, Director Cell Therapy Facility
H. Lee Moffitt Cancer Center & Research Institute
Tumor Infiltrating Lymphocytes: Streamlining Manufacturing for
Multi-Center Clinical Trials and Commercialization

Abstract

The 21st Century Cures Act and the FDA mandate for accelerating the approval process for cellular therapies has an impact on the approach to GMP manufacturing for early-phase clinical trials. We have embraced an academic and industry partnership to facilitate multicenter clinical trials using tumor infiltrating lymphocytes (TIL) for solid tumors. Through a combination of process improvements intended to shorten product manufacturing time, as well as innovative implementation of GMP practices, we have maximized the contribution of academic and contract manufacturing organizations to support multiple ongoing trials intended to receive FDA approval for a new cellular therapy.

Biography

Dr. Kelley, Cell Therapy Facility Director, is a Senior Member at Moffitt Cancer Center and Professor at the University of South Florida. Dr. Kelley has provided leadership for cellular therapy facilities for over twenty years at three institutions: University of Utah, Dana Farber Cancer Institute, and Moffitt Cancer Center. She received graduate and postdoctoral training in immunology and hematology from Vanderbilt University, Nashville, Tennessee. Her scientific career evolved from a fundamental interest in immunological mechanisms of T lymphocyte function, growth mechanisms of hematopoietic stem and progenitor cells, and molecular changes associated with malignant transformation. Knowledge of the hematopoietic system led to an interest in stem cell biology and therapies. As director of the Cell Therapy Facility at the University of Utah from 1994–2011, she was responsible for developing and expanding a Cell Therapy and Regenerative Medicine Laboratory. During her tenure she was responsible for pre-clinical and clinical cell therapy product development to support investigational new drug (IND) applications for the production of allogeneic mesenchymal stromal cells (MSCs), autologous bone marrow-derived mononuclear cells, and allogeneic fetal-derived oligodendrocytes. As director of the Cell Manipulation Core Facility at the Dana Farber Cancer Institute at Harvard from 2011–2012, she oversaw management of 20 FDA-approved INDs for the manufacture of gene-modified CD34+ cells, tumor cell vaccines, dendritic cells, MSCs, and others. As director of the Cell Therapy Facility at Moffitt Cancer Center, she oversees 22 active INDs for a variety of cell therapy products, largely to support immunotherapy for adult and pediatric patients. She currently serves as the Principal Investigator for Production Assistance for Cellular Therapies (PACT) – Cell Processing Facilities to perform pre-clinical cell therapy product development in collaboration with the National Heart, Lung, and Blood Institute (NHLBI) and other PACT Centers, and as Core Laboratory Technical Director for the Moffitt Cancer Center Support Grant. Dr. Kelley excels at bridging the gap between laboratory-based discoveries and new therapies for patients.

Jon Ellis
Senior Director Technical Services, Thermogenesis Corp.
Automated, Closed System Manufacturing of CAR T-Cells

Abstract

The field of cancer immunotherapy has been revolutionized by the application of chimeric antigen receptor (CAR) T-cell therapy in hematologic cancers. These CAR T-cells are engineered to express synthetic receptors that redirect polyclonal T-cells to surface antigens for subsequent tumor elimination. Despite the remarkable success of this form of immunotherapy, and even the recent granting of Biologic Licenses by the FDA to Novartis and Kite, the methods of manufacturing these clinical doses of genetically modifed T-cells are predominately manual, reliant on open systems that are highly variable in yield and very expensive. These limitations in processing quality are compounded by the fact that these are very sick patients who do not provide normal collections of cells to process. Automation of the processing steps utilizing closed systems is required to improve the quality of the clinical doses as well as reducing the cost of the therapy so it can be available for all patients in need. Thermogenesis has made progress in accomplishing this goal.


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