Enabling Technology in Cell-Based Therapies: Scale-Up, Scale-Out, or Program In-Place

Those of us working in clinical and medical technology and automation are most enthusiastic about our work when the instruments and techniques we are developing will directly affect patient well-being. The recent arrival of FDA-approved chimeric antigen receptor (CAR) T-cell therapies^1,2 and the further expansion of T-cell and other cell-based therapies beyond oncology applications have reinvigorated discussions around the ways in which we harvest, culture, process, or directly alter therapeutic cells. However, the manufacturing process (i.e., selection of peripheral blood mononuclear cells from whole blood, activation of T cells, transduction with CAR viral vectors or transposons, and expansion in an appropriate bioreactor) for combination gene/cell therapies such as CAR T is complex, and there remain many opportunities for improvements to decrease the cost and improve the safety of these important new clinical tools. In this SLAS Technology special issue titled “Enabling Technology in Cell-Based Therapies: Scale-Up, Scale-Out, or Program In-Place,” we highlight technologies that are changing the ways in which researchers and clinicians process and use therapeutic cells.

One of the major technology areas with the potential to simplify and decrease the costs associated with harvesting and processing therapeutic cells is the technique used to select and separate the cells with the greatest therapeutic potential from the complex mixtures of cells in harvested blood and expanded cultures. While the culture reactors that the cells are loaded into for expansion have become closed and automated systems, the separation techniques for selecting and monitoring those cells have remained dependent on traditional technologies, such as centrifugation, fluorescence-activated cell sorting, and magnetic-activated cell sorting. New techniques that utilize “smart” dynamic magnetic traps,³ microfluidic separators,⁴ and acoustic energy-based⁵ cell separation techniques provide new inline and closed-loop systems that may be directly integrated with the rest of the cell culture and processing machinery.

In this issue, three groups present methods of cell separation that utilize unique microscale forces that were originally developed for research and diagnostic applications that are in the process of being scaled-up (i.e., developed for use with either higher cell concentrations or large sample volumes) for industrial applications.^3–5 Each technology has unique challenges to successfully “scale-up,” and specific advantages within industrial processes, such as label-free, quantitative, or biophysical versus molecular separation mechanisms. The authors of each separation technology share progress in overcoming these challenges, while presenting new device packages and footprints that may be more easily integrated into inline and online cell processing equipment.

Other processes in addition to cell separation will need to be adapted to provide the ability to continually alter^6,7 the cell state during the expansion of cells within bioreactors to improve cell manufacturing, while reducing cost. In this issue, two research articles describe methods to better automate or package complex cell manipulations into closed bioreactor systems. One group describes a method to automatically control sizes of stem cell aggregates within automated culturing systems, while another describes unique polymeric electrode systems that may be built directly into processing systems for applications such as electrical cell lysis and electrokinetic molecular separations.

In addition to modifying processes that alter cell state, improved cell manufacturing systems will need to maintain the capability to monitor cell product quality. In the final technical report within this issue, the authors present methods to rapidly sample and analyze cell culture media to detect the presence of unwanted microorganisms,⁸ demonstrating the first steps toward building inline sterility tests that may be implemented directly within new cell manufacturing bioreactor systems.

Finally, this issue contains two review articles that detail the status of cell bioreactors in both stem cell⁹ and tissue/organ engineering¹⁰ applications, thus providing the user with the tools to think about how the new processing technologies described may find their place in a variety of commercial cell therapy and manufacturing systems.