Investigating Safety and Toxicity of Advanced Therapies (iSTAT)

Advanced therapies based on human pluripotent stem cell (hPSC)-derived cellular products hold great promise for treatment of various currently incurable diseases. The capacity of hPSCs to generate large quantities of diverse, clinically relevant cell types is essential for the development of these advanced therapies. Clinical trials employing hPSC-derived differentiated cells are currently underway for a range of conditions, including macular degeneration, Parkinson’s disease and spinal cord injury, with many more on the horizon. However, a significant safety concern that stands to seriously jeopardise a successful translation of hPSC-based therapies is the takeover of cultures by genetically abnormal cells. It is now well documented that the scale-up of hPSCs for downstream applications inevitably causes genetic alterations, ranging from karyotypic abnormalities to single nucleotide variants, some of which have been associated with cancer. Such aberrations raise safety concerns, particularly regarding potential tumorigenicity of cell therapies upon transplantation into patients. Therefore, the primary concern in the context of regenerative medicine is ensuring that hPSCs or their differentiated derivatives do not harbour variant cells that would pose a risk of tumour formation upon transplantation. Nonetheless, it remains unknown which aberrations constitute a risk to patients and which are inconsequential for the safety of cell therapies. Moreover, current in vivo tumorigenicity assays have significant shortcomings as they are time-consuming, expensive and may not accurately predict human tumorigenicity due to species differences. The overarching goal of this collaborative program is to mitigate the risks associated with cellular therapies by establishing reliable pre-clinical models for evaluating the safety of these therapies and minimizing the occurrence of variant hPSCs during expansion. This will involve the development of standardized assays and tools for advanced therapies, to provide developers and regulators with the information they need to more swiftly move these potentially transformative medicines forward and to patients in need. Access to standardised safety testing methods will reduce risk of product development by establishing clear expectations of what is deemed acceptable by regulatory agencies for advanced therapy for early-stage clinical programs. Moreover, standardized methods will reduce the need for redundant investments in assay development and validation that are currently contributing to the high cost of advanced therapy development and manufacture. This Prosperity Partnership builds on the significant successes of the UK Regenerative Medicine Platform and provides a framework for new solutions to key safety challenges for advanced therapies. Recognising the importance of interdisciplinary collaboration in addressing these complex issues our Partnership brings together exceptional cross-disciplinary investigators alongside extensive industry participation. The substantial involvement of industry partners underscores the critical need for solutions to the challenges our Partnership addresses, demonstrating strong industry buy-in. Our partners are leading companies in cell therapy, already performing hPSC-based clinical trials, tool/media developers and Contract Development and Manufacturing Organizations (CDMOs) for cell therapy manufacturing. Together, our activities will directly contribute to solidifying the UK’s position as a global leader in advanced therapy, driving innovation, improving patient outcomes, and contributing to economic growth.