The Challenge of Variability in Chimeric Antigen Receptor T cell Manufacturing.

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.