Advanced non-animal models in biomedical research : immunogenicity testing for advanced therapy medicinal products

Advanced therapy medicinal products (ATMPs) are a fast-growing class of innovative biological products. They include somatic cell therapy, gene therapy, tissue-engineering and their combinations, and they hold the key for new treatments for rare diseases and the establishment of personalised medicine. Nevertheless, several hurdles are currently hampering the faster development and wider clinical use of ATMPs, one of which is safety and their immunogenic potential. Testing for immunogenicity of cell-based, gene-based or tissue-engineered products in animals has uncovered the intricate limitations of in vivo models. There is, therefore, a growing need for innovative non-animal methods to better mimic patient immune responses to ATMPs. The JRC's EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) conducted a study to review the state-of-the art of advanced non-animal models used in immunogenicity testing for ATMPs. The majority of the 88 models that were identified were based on in vitro techniques with a limited amount of in silico methods, and most of these focused on the investigation of cell therapy products. Furthermore, most of the identified methods used classical 2D primary cell cultures in a low throughput format, typically yielding limited amounts of measurement information. This review highlights a pressing need for the development and acceptance of more sophisticated and innovative non-animal approaches in this field which will pave the way for the broader use of ATMPs in the clinic.