Potency Assays for Advanced Stem Cell Therapy Medicinal Products

✍ Scribed by Jorge S. Burns

• Publisher: Springer
• Year: 2023
• Tongue: English
• Leaves: 226
• Series: Advances in Experimental Medicine and Biology, 1420
• Category: Library

✦ Synopsis

This volume of the Springer book series Advances in Experimental Medicine and Biology covers potency assays, one of the most complex yet fundamental evaluations that critically influence stem cell regenerative medicine. Developing potency assays for cell-based medicinal products comes with numerous challenges due to the highly specialised nature of the application and purpose. This book provides the reader with the knowledge necessary to understand issues governing the successful development of potency assays, highlighting an international outlook of how the various challenges raised are being managed. Stakeholders concerned with potency assay development range from patient and clinician to contract research organisations, small and medium enterprise, regulatory authorities and even politicians. The value of potency assays is poised to increase given the inevitable watershed as early-stage clinical trials addressing safety progress to trials testing efficacy. Contributors from clinical, academic, industrial and regulatory sectors establish a broad point of view for guidance and timely debate. Potency assays require extensive collaboration across disciplines and sectors, as well as compromise and the authors aim to constructively address the many key aspects involved.

Potency assays provide a quantitative measure of the biological activity of advanced therapy medicinal products (ATMPs) and thus are required for their market authorization. As the pace of ATMP development accelerates, the need to develop specific, accurate, and robust potency assays for each product is also accelerating. The volume Potency Assays for Stem Cell Advanced Therapy Medicinal Products presents a broad outlook on the development, quality attributes, and implementation of potency assays for ATMPs. The first few chapters introduce a nuanced historical perspective on the science of potency assay development, describe specific quality attributes of an idealized potency assay, indicate pitfalls associated with developing such assays for ATMPs, and review guidance recommended by regulatory authorities on assay suitability for product approval. Subsequent chapters highlight efforts to develop potency assays for specific ATMPs, including skeletal stem cells, mesenchymal stromal cells, extracellular vesicles, CAR T-cells, and discuss emerging technologies/platforms for potency assay design. The volume concludes with a chapter reviewing potency assays used for the release of commercial ATMP products, which amalgamates information contained in previous chapters. Overall, the knowledge contributed from leading authorities in both academia and industry is an ideal resource for technicians, scientists, clinicians, process engineers, and regulators working with ATMPs.

―Donald G. Phinney, PhD Professor,  Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology

 

✦ Table of Contents

Preface
Contents
Contributors
About the Editor
1: The Art of Stem Cell-Based Therapy
1.1 The Dawn of a New Era
1.2 Lessons from a Past Disease
1.3 Potency Assays for Modern Disease Intervention
1.4 From Viral Vaccination to Safe Therapy with Cells
1.5 From Stem Cell Safety and Efficacy to Potency
1.6 Complementing Stem Cell-Based Therapy Art with Standard Operating Procedures
References
2: Potency Assay Development: A Keystone for Clinical Use
2.1 Potency Assays as Part of Cell-Based ATMP Quality Control Testing
2.1.1 What Is a Potency Assay?
2.1.2 Regulatory Requirements for a Potency Assay
2.2 Approach to Develop a Potency Assay for Cell-Based ATMPs
2.2.1 General Considerations
2.2.2 Progressive Implementation of a Potency Assay
2.3 Clinical Value of Potency Assays
2.3.1 Relationship Between Potency and Clinical Efficacy
2.3.2 Potency and Defining an Effective Dose for ATMPs
2.4 Potency Assay in Product and Process Development
2.4.1 Stability Studies
2.4.2 Comparability Studies
2.4.3 Compatibility Studies
2.5 State of the Art of Potency Assays for Cell-Based ATMPs
2.5.1 Examples of Potency Assays for Cell-Based ATMPs
2.5.2 Challenges to Potency Assay Development for ATMPs
2.6 Conclusion
References
3: Potency Assays: The ‘Bugaboo’ of Stem Cell Therapy
3.1 Potency – What a Cell Can Do
3.2 Relevance of Potency Assays
3.3 Regulatory Requirements
3.3.1 EMA Regulatory Requirements
3.3.2 FDA Regulatory Requirements
3.3.3 Japanese FDA Regulatory Requirements
3.4 Development of Potency Assays
3.4.1 Use of Surrogate Markers
3.4.2 Autologous and Allogeneic Products
3.4.3 Standardisation of Assays
3.4.4 Further Considerations
3.5 The Quality Target Product Profile
3.6 Final Remarks
References
4: Identifying Biomarkers for Osteogenic Potency Assay Development
4.1 Skeletal Stem Cell for Conservative Bone Healing
4.2 The Challenge of hBM-MSC Donor-Specific Heterogeneity
4.3 Telomerised MSC; Scalable Clonal Populations with Consistent Bone-Forming Potential
4.4 Comparative Analysis of Gene Expression, microRNA, Morphological Phenotypes and Cell Membrane or Secreted Proteins
4.5 Compelling Pathways for Functional Attributes in Osteogenic Potency Assays
4.6 Lessons Learned for Bone Repair ATMP Development
References
5: Potency Assay Considerations for Cartilage Repair, Osteoarthritis and Use of Extracellular Vesicles
5.1 Articular Cartilage
5.2 Cell-Based Treatment of Cartilage Defects
5.2.1 Potency Assays Used for Autologous Chondrocyte Implantation
5.2.2 Mechanism of Action (MoA) of MSC-Based Cartilage Defect Repair
5.2.3 MoA: Differentiation Versus Paracrine Signalling
5.2.4 Cell Fate of MSCs Used to Treat Cartilage Defects
5.3 Considerations and Suggestions for Potency Assays for MSC-Based Cartilage Defect Repair
5.3.1 Potency Assays for Differentiation
5.4 Treatment of Osteoarthritis
5.4.1 MSC-Based Treatment of Osteoarthritis
5.4.2 Tracking MSC After Intra-Articular Injection in Osteoarthritic Joint
5.5 Considerations and Suggestions for Potency Assays for MSC-Based Treatment of Osteoarthritis
5.5.1 Effects on Macrophage Polarisation
5.5.2 Effects on NK Cells
5.5.3 Effects on T Cells
5.5.4 Effects on B Cells
5.5.5 Effects on Cartilage Formation
5.5.6 Possible Surrogate Potency Markers
5.6 Extracellular Vesicles
5.6.1 Functional Assays for EVs
5.7 Summary
References
6: Advanced Technologies for Potency Assay Measurement
6.1 Introduction
6.2 Variability of MSC Therapeutics
6.3 General Considerations for MSC Release Criteria
6.4 Key Aspects of Potency Assays
6.5 Potency Assay Technologies
6.5.1 Immunological Assays
6.5.2 Genomic Assays
6.5.3 Secretome Assays
6.5.4 Phosphorylation Assays
6.5.5 Morphological Profiling Assays
6.5.6 Biomaterial-Based Assays
6.5.7 Angiogenic Assays
6.5.8 Metabolic Assays
6.6 Conclusion
References
7: Innovative Quantification of Critical Quality Attributes
7.1 Introduction
7.2 Lab-on-PCB
7.2.1 PCB Technology Overview
7.2.2 Early Prototypes
7.2.3 Materials and Processes for Microfluidic Integration
7.2.3.1 Hybrid Polymer/Si – PCB Integration Approaches
7.2.3.2 Dry Film Photoresist Seamless Integration
7.2.4 Advanced Quantification Diagnostic Device Examples
7.2.4.1 PCR Modules
7.2.4.2 Advanced Bio-Sensing Devices
7.2.5 Recent Developments in Lab-on-PCB Commercially Relevant Issues
7.3 Conclusion
References
8: Release Assays and Potency Assays for CAR T-Cell Interventions
8.1 Introduction
8.2 Regulations and Requirements for Quality Control Testing and Batch Release
8.3 Safety
8.3.1 Sterility Assessment
8.3.2 Mycoplasma Detection
8.3.3 Replication Competent Lentivirus (RCL) or Retrovirus (RCR)
8.3.4 Vector Copy Number (VCN) per Transduced Cell
8.3.5 Identity
8.3.6 Purity
8.3.7 Quantity
8.4 Potency
8.4.1 Potency Assessment for CAR T-Cell Therapies
8.5 Regulatory Aspects
8.6 Methods for Potency Assessment of CAR T-Cell Products
8.6.1 Target-Directed Cytotoxic Activity
8.6.2 Direct Assays
8.6.3 Indirect Assays
8.6.4 Immunophenotyping
8.6.5 Target-Induced Proliferation
8.6.6 Polyfunctionality
8.7 Challenges and Potential Improvements for CAR T-Cell Potency Assays
8.8 Future Challenges and Directions for CAR T-Cell Product Release Testing
References
9: Illustrative Potency Assay Examples from Approved Therapies
9.1 Introduction
9.2 Regulatory Framework
9.3 CAR-T: Super T Cells to Fight Cancer
9.3.1 Description and Indication
9.3.2 Characterization of Tisagenlecleucel Product KYMRIAH®
9.4 Holoclar®: A Tissue Engineering Product to Regenerate Cornea
9.4.1 Description and Indication
9.4.2 Characterization of Limbal Epithelial Stem Cell Product Holocar®
9.5 Remestemcel-L: MSC for the Management of GvHD
9.5.1 Description and Indication
9.5.2 Characterization of Remestemcel-L Product PROCHYMAL® (or RYONCIL™)
9.6 Addressing Potency in Other Selected ATMP
9.6.1 Approved ATMP
9.6.2 ATMP Under Clinical Investigation
9.7 The Case of Pluripotent Stem Cells
9.8 Final Remarks
References
10: From the Integrity of Potency Assays to Safe Clinical Intervention: Legal Perspectives
10.1 Introduction
10.2 The Evolving Regulatory Concept of Potency
10.3 The Emergence of the Regulatory Landscape for Stem Cell-Based ATMPs and Their Potency Assays
10.4 Overview of the Current EU Regulatory Framework for Stem Cell-Based Therapies
10.4.1 ATMP Regulation Covering the Market Access, Supervision and Pharmacovigilance of Advanced Therapies
10.4.2 Allogeneic or Autologous: Does the Origin of the Source Materials Affect the Process?
10.4.3 EU Clinical Trials Regulation Streamlining the Application Procedure
10.4.4 “Soft Law” Encountering “Hard Science”: Flexibilities Are Needed to Deal with Rapid Scientific Advancements in an Ethically Sensitive Field
10.4.5 EU “Soft Law” Levelling the Playing Field for Potency Assay Developers
10.5 Conclusions
References
11: The Evolving Landscape of Potency Assays
11.1 Getting Potency Assays Just Right
11.2 Finessing the Potency of ATMP
11.3 Potency Assays for Acellular Products
11.4 Cryopreservation and Scale-Up: Balancing Complexity and Product Quality
11.5 Highlighting COGS in the Wheel of CAR T-Cell Therapy
11.6 Potency Assays for Induced MSC
11.7 Enhancing Potency Assays: Cell Priming, Nanotechnology and 3D Culture
11.8 Regulations, Guidelines and Evolving Institutional Roles
References
Glossary of Abbreviations
Index