Autologous t cell therapy products: tech transfer to gmp and quality by design in new zealand

Background & Aim Over the past decade, rapid advancements in cell and gene therapies have led to nearly 1000 ongoing clinical trials focusing on cell-based immune-oncology. However, most of these trials are confined to pilot phases I and II, as further translation has been limited by the challenges of large scale manufacture of "living" drug products, while maintaining safety and cost-effectiveness. Despite a promising list of FDA-Approved Cellular and Gene Therapy Products, including six CAR T-cell cancer therapies and two cell-based gene therapies for sickle cell disease, the intrinsic variability between products impedes development of general standards applicable across distinct manufacturing facilities and processes.In this context, the Quality by Design (QbD) approach emerges as a pivotal strategy, introducing the notion of in-process quality development and management, based on sound understanding and control of the production and its variables.Here we report a case study involving the development of an autologous Antigen-Specific T cell (AST) product within our facility, based on a BioSpherix XVIVO X2 Closed Incubation System. This case serves as a QbD example for tech transfer into a therapeutic immuno-oncology product, taking into account unique local constraints. Methods, Results & Conclusion Our laboratory has optimized a protocol for ex vivo expansion of autologous effector T cells targeting the PRAME antigen (Fig. 1A), suitable for GMP manufacturing and downstream treatment of melanoma patients in a Phase 0 clinical trial. Following a QbD approach, the manufacturing process has been divided into five main unit operations (Fig. 1B), to separately address Critical Process Parameters (CPPs) impacting the Critical Quality Attributes (CQAs) of our AST product. Parameters such as starting material phenotype (Fig. 1C), length of priming stimulation, cytokine combination and concentration, amongst others, have been assessed in pre-clinical in vitro studies. A similar approach, aiming at characterizing intrinsic process variability and defining production standards applicable to patient-derived samples, is under development across all unit operations, to progressively optimize each manufacturing step.In this era of rapid advancements in cell and gene therapies worldwide, we wish to bring New Zealand one step forward in making these innovative therapies locally accessible, with remarkable impact on national healthcare/standard of care.