by the JSRM-ISCT iPSC Joint Committee
JSRM-ISCT iPSC Joint Committee was established in December 2021, aiming to support the dissemination of iPSC-derived cell products as an emerging therapeutic platform in the field of cell therapy, alongside CAR-T and MSC therapies. The committee is co-chaired on the JSRM side by Shin Kaneko, Professor at the CiRA foundation for iPSC Research, and on the ISCT side by Shin Kawamata, CEO of Cyto-Facto, a CMO/CDMO company for cell therapy. The Committee’s membership has been expanding since its establishment and currently comprises 22 KOLs representing a variety of organizations: translational alliances (GAiT), translational research institutions (Peter MacCallum Cancer Center, CiRA), governmental research biosafety institutions (NIH, NIHS Japan), global reagent/equipment suppliers (Thermo Fisher), several biotech companies (Aspen Neuroscience), and several academic ones.
This Committee focuses on the therapeutic, industrial, and commercial aspects of iPSC-based therapy, including the analysis of clinical data and outcomes, the manufacturing of iPSC-derivatives in process development, the technology for intermediate products, the cost of goods, and global regulatory considerations for conducting multinational clinical trials. This distinguishes the Committee from other collaborations in the space that focus on the basic science for stem cell biology. The Committee contributes to the organization of joint JSRM-ISCT seminars and participates in developing the program of regional and annual meetings for ISCT and JSRM, and collaborates with ISCT Early Stage Professionals (ESPs) to mentor the next generation for the field. Recently, the committee had its first white paper on iPSC-based cell therapy accepted for publication in Cytotherapy.
The activities of the committee in 2022-2024
1. Organized a roundtable at ISCT 2022 San Francisco entitled ‘Expectations and Challenges for iPSC Based Cell Therapies’
2. The first JSRM-ISCT Joint iPSC Committee Symposium dated 2022 1203 in Tokyo
Theme: global regulatory land scape for iPSC-based cell therapy
JSRM speakers: Yoji Sato (NIHS), Jun Takahashi (CiRA), Yoshiaki Maruyama (PMDA)
ISCT speakers: Christiane Niederlaender (Parexel international), Zhaohui Ye (FDA), Melissa Carpenter (ElevateBio)
3. Organized a roundtable at ISCT 2023 Paris entitled ‘Overcoming Barriers to iPSC Market Readiness: Part II’
4. Published a position paper related to iPSC-based cell therapy in Cytotherapy
Title: Considerations for the development of iPSC-derived cell therapies: A review of key challenges by the JSRM-ISCT iPSC Committee
The paper deals with the practical aspects of iPSC-based cell therapy, covering the diversity and complexity of global regulatory frameworks for iPSC-based therapies related to required preclinical safety test sets, and design for clinical trials. Quality control requirements for iPSCs and iPSC-derivatives are also discussed, alongside safety issues, including permissible genomic instability, genomic mutation, donor infection episodes for allogenic application, the minimum QC test menu, tumorigenicity test design and additional requirements for gene editing. Case studies on cost of Goods for iPSCs and iPSC-derivatives are described in the paper as well. This article is currently available in press at: https://www.isct-cytotherapy.org/article/S1465-3249(24)00730-8/fulltext
5. Organized a roundtable at ISCT 2024 Vancouver entitled ‘Accelerating iPSC-based Therapeutic Development: The Case for Harmonizing Regulatory Requirements’
6. The JSRM-ISCT iPSC Committee organized the iPSC Scientific Signature Series event, which took place at the ISCT 2024 annual meeting in Vancouver. This series provided a comprehensive exploration of the current state and future directions of iPSC therapies. The format centered around discussions amongst invited key opinion leaders, with presentations setting the stage during each session, and was attended by an audience of over 150 people. Topics covered included manufacturing considerations for autologous and allogeneic iPSC-derived therapies, practical and regulatory aspects of CMC strategy, genome-wide analysis of iPSC-derived cell therapies, the regulatory landscape of iPSC-derived product development, and insights from ongoing clinical trials.
Session I: Manufacturing Considerations for Autologous and Allogeneic iPSC-derived Therapies & Opportunities for Cross-industry Alignment
During the session on manufacturing considerations for autologous and allogeneic iPSC-derived therapies, chaired by Dr. Bruno Marques, experts from different organizations (e.g., CDMO, drug development, technology provider) shared insights into the complexities and advancements in the field. Dr. Lise Munsie from CCRM emphasized the importance of quality and documentation in cell banking for allogeneic therapies, detailing the structure and risk profiles of seed and master cell banks. She discussed regulatory considerations and the associated costs of producing these banks under GMP conditions. Mr. Kim Raineri from Aspen Neuroscience presented an autologous approach to treat Parkinson’s disease, focusing on the criticality of starting material quality and the role of automation in their manufacturing process. He highlighted the significance of a genetic stability testing strategy to supply clinical trials. Dr. Priye Iworima from PBS Biotech explored bioreactor technology for scalable and efficient cell culture, providing a case study of insulin-producing cell therapy. She emphasized process variability, the need for favorable hydrodynamics in bioreactors, and the integration of advanced analytics to enhance process understanding. The panel highlighted opportunities for cross-industry alignment to streamline manufacturing and regulatory practices.
Session II: CMC: Developing Effective Strategies to Control and Assess Identity & Potency Throughout the iPSC-derived Product Lifecycle
This session, chaired by Jo Mountford (SNBTS, UK) focused on the practical and regulatory considerations underpinning CMC (Chemistry, Manufacturing, and Controls) strategy for the manufacture of iPSC-derived products. Jacqueline Barry (CGTC, UK) provided an excellent overview of the CMC journey, emphasising the importance of quality and compliance from the start of the development process. Jacqui also stressed the need for proper validation, documentation, and traceability in GMP environments, and advocated for using GMP standards for all banking operations to ensure long-term usability and compliance.
Ricardo Baptista (SmartCella, Sweden) took a more in depth look at how to put together a CMC plan, he shared strategies for de-risking product development and the stated the importance of defining a quality target product profile (qTPP). Ricardo also discussed the use of process diagnostics and risk assessment, coupled with the application of QbD approaches, to continuously refine and improve manufacturing processes.
To conclude Nobuaki Shiraki (Tokyo Institute of Technology, Japan) shared his elegant work that shows how medium components, including zinc and methionine, modulate maintenance of pluripotency and promotion differentiation. These findings highlight the potential for metabolic regulation to improve the control of iPSC-derived product manufacturing.
The take home message of this session was definitely that ‘one must always start with the end in mind’ when planning the CMC strategy for a new product, and that it is never too early to start compiling the qTPP as the contents of this document will direct much of the development plan.
Session III: Characterization of iPSC-derived Cell Therapies – Going in Depth
In the session chaired by Dr. Xiaokui Zhang from Aspen Neuroscience, experts delved into the genome-wide analysis of iPSC-derived cell therapies. Dr. Jason 'Jay' Mills from Century Therapeutics discussed the need for extensive risk analysis and evaluation followed by establishing a pipeline of comprehensive genomic characterization assays, such as SNP arrays, short-read and long-read WGS, targeted locus amplification technology, to detect various genetic variants and to ensure safety and precision during multiple gene edits, single cell cloning and extended iPSC culturing. Dr. Shin Kawamata from Cyto-Facto highlighted the risks associated with long-term iPSC culture, advocating for strategies to minimize cell mitosis and maintain genomic stability by controlling the maximum number of CVNs to not exceed 3. Mr. Daniel Fremgen from Aspen Neuroscience presented on using machine learning models to predict functional attributes such as dopamine release and engraftment potential in iPSC-derived dopaminergic neuron precursor cells. He stressed the importance of high-quality datasets for training these models and ensuring data consistency. The session underscored the necessity of forward-thinking approaches to build robust analytical pipelines, minimize risks associated with genome instability, and implement standardized QC methods to ensure the safety and efficacy of iPSC-derived cell therapies.
Session IV: Regulatory Requirements and Heterogeneity Across Jurisdictions
At the ISCT 2024 iPSC Signature Series session, chaired by Dr. Wanxing Cui from Georgetown University Hospital, regulatory experts Mr. Yusuke Nozaki from PMDA and Dr. Zhaohui Ye from the FDA delved into the intricate regulatory landscape of iPSC-derived product development. Key points included the emphasis on scalability, quality control, and batch consistency for autologous and allogeneic iPSC therapies. They highlighted the importance of early engagement with regulators and comprehensive justification for starting materials and process changes. Discussions also focused on the necessity and extent of genomic stability testing, balancing mutation detection with clinical relevance, and the role of AI in this context. The session underscored the critical need for international collaboration to harmonize regulatory standards, particularly in genomic stability and potency assays, and emphasized developing robust testing frameworks to ensure safety and efficacy. Reflecting on Dr. Yamanaka's vision, the session concluded by stressing ethical considerations, patient-specific therapy, and the importance of ongoing collaboration in the field.
Session V: Ongoing Clinical Trials
In the ongoing clinical trials session chaired by Dr. Shin Kawamata from Cyto-Facto, Japan, speakers shared insights into their target diseases, current trial statuses, and regulatory roadmaps. Dr. Narihito Nagoshi elucidated the mechanisms of neurological recovery in spinal cord injury through preclinical research on the transplantation of iPS-derived neural precursor cells. He has now advanced to clinical trials, applying this transplantation therapy to actual patients. Dr. Kilian Kelly from Cynata Therapeutics, Australia, highlighted multiple therapeutic areas, including acute graft versus host disease (aGvHD) with a Phase 1 trial showing an 87% overall response and 60% 2-year overall survival, ongoing Phase 1 trials for diabetic foot ulcers (DFU), and a Phase 3 trial for osteoarthritis, all aimed at future regulatory approval and commercialization. Dr. Dan Kemp of Shinobi Therapeutics, USA, presented on immune evasive iPSC therapies, focused on preclinical development of its allogeneic Katana iPS-T cell platform. Dr. Kiyoko Bando from Sumitomo Pharma introduced the company’s business strategy and highlighted the development for iPS-retinal pigment epithelium (RPE) cells. To accelerate delivery of the therapy to patients, RPE tears was selected as the first indication, aiming to expand indications thereafter.
The session also explored benchmarks for exit strategy for start-ups, cost considerations for iPSC-based products, and the use of iPSCs with low immune rejection.
The ISCT 2024 iPSC Scientific Signature Series underscored the transformative potential of iPSC-derived therapies across various medical conditions and highlighted the critical challenges and innovations driving the field forward. Key takeaways included the paramount importance of early and rigorous quality control, the integration of advanced technologies like automation and AI, and the necessity of robust regulatory frameworks to ensure safety and efficacy. The discussions illuminated the path towards more effective and scalable iPSC-derived treatments, emphasizing the need for continuous collaboration between industry, academia, and regulatory bodies. As the field progresses, the insights and strategies shared during these sessions will play a crucial role in overcoming existing hurdles and advancing the development of life-saving therapies, contributing to the ongoing work of the JSRM-ISCT iPSC Committee.
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