Digital twin-assisted process design for NK-cell therapies

• Applicants: Dr. Werner Dammermann; Professor Dr.-Ing. Ralf Pörtner
• Subject Area: Biological Process Engineering
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493579396

Human immune cells, including natural killer (NK) cells, have been produced using Advanced Therapy Medicinal Products (ATMP) guidelines and have been tested in clinical studies for various diseases. Within the, mostly patient specific, manufacturing workflow for generation of the required amount of functional NK cells, clinicalgrade purity and ex vivo expansion are crucial. The final in vivo therapeutic efficacy of a cell product depends to a large extent on the manufacturing process. The objective of the project is to investigate on a basic science level (A) the impact of process conditions for cell proliferation on the functionality and Critical Quality Attributes (CQAs) of NK cells and (B) the digital twin-assisted linkage of therapy-relevant cell properties (initial CQAs - iCQAs) with process parameters (CPPs). The final goal is to evaluate if digital twins, in form of combinations of mathematical models and statistical methods, facilitate a fast and efficient design of the production processes for cell therapeutics using NK-cells as a model cell population. Due to the high complexity of the required investigations, experimental and digital twin-assisted tools will be combined leading to an increased process understanding with reduced number of experiments and therefore decreased investigation time and costs. The impact of process conditions such as batch/perfusion, oxygen concentration or substrate concentration (e.g. glucose) will be studied within appropriate, well characterized (by Computational Fluid Dynamics) cultivation systems. Mathematical modeling for digital twin generation will be formulated for the individual process steps (cell expansion, design of bioprocess, bioreactor operation, etc.). The ultimate target of our approach is to produce NK-cells which actively kill cancer cells. Experimentally, the proof of biological activity comprises the testing of the manufactured NK- cells in immunocompromised mice which harbour human tumours. As this test would be beyond the scope of this project, we will characterize the cells with a panel of monoclonal antibodies which recognize biologically important molecules in this process. For this purpose, the analysis of samples at the beginning, during the process (in-process-control) and at the end is mandatory. This digital twin assisted approach could be a methodological and knowledge management platform for a framework for a donor specific and knowledge-based process development for next generation ATMP´s.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Co-Investigator: Professor Dr. Udo Schumacher
• Cooperation Partner: Professor Dr. Christoph Herwig