The Challenge of Variability in Chimeric Antigen Receptor T Cell Manufacturing

Abstract

Abstract: Autologous chimeric antigen receptor (CAR) T cell manufacturing involves the modification and expansion of T cells obtained by apheresis collection from a patient. The mechanism of apheresis collection and the specific clinical features seen in these patients combine to generate apheresis products with high variability of content. Manufacturers often attempt to minimize this variability such that processes can be standardize in accordance with Good Manufacturing Practices (GMP). Such standardization improves efficiency and helps to ensure robustness of the overall process. Apheresis product variability can negatively impact T cell manufacturing success. Patient- and collection-driven variability often leads to non-T cells entering the apheresis product. Many of these cells can directly or indirectly impair T cell activation and expansion, decreasing the manufacturing success rate. Therefore, patient-driven variability observed in apheresis products must be mitigated through downstream processing. T cell enrichment is one step in the manufacturing cycle that can reduce process variability by generating more uniform downstream material. However, current T cell enrichment methods have limitations. Much of this type of variability can be avoided by collecting patients earlier in their disease or treatment course; this is not current, widespread, or standard practice. While variability poses challenges to successful CAR T cell manufacturing and mitigation strategies can be successful, more work is needed in this area. Lay Summary: Apheresis collection is a method of obtaining large numbers of cells to start the CAR T cell manufacturing process. Because patients are highly variable in their presentation, some with more or less cells in their blood, the apheresis product will reflect this with more or less cells in the bag. This poses problems with the manufacturer who wants to perform uniform processing. There are ways to combat this variability; however, current techniques are limited and additional work is needed to develop better ways to do this. Collecting patients earlier may improve this, but it is not standard practice to date.