No abstract
Chimeric antigen receptor T (CAR‐T) cell therapy is rapidly becoming a frontline cancer therapy. However, the manufacturing process is time‐, labor‐ and cost‐intensive, and it suffers from significant bottlenecks. Many CAR‐T products fail to reach the viability release criteria set by regulators for commercial cell therapy products. This results in non‐recoupable costs for the manufacturer and is detrimental to patients who may not receive their scheduled treatment or receive out‐of‐specification suboptimal formulation. It is demonstrated here that inertial microfluidics can, within minutes, efficiently deplete nonviable cells from low‐viability CAR‐T cell products. The percentage of viable cells increases from 40% (SD ± 0.12) to 71% (SD ± 0.09) for untransduced T cells and from 51% (SD ± 0.12) to 71% (SD ± 0.09) for CAR‐T cells, which meets the clinical trials’ release parameters. In addition, the processing of CAR‐T cells formulated in CryStor yields a 91% reduction in the amount of the cryoprotectant dimethyl sulfoxide. Inertial microfluidic processing has no detrimental effects on the proliferation and cytotoxicity of CAR‐T cells. Interestingly, ≈50% of T‐regulatory and T‐suppressor cells are depleted, suggesting the potential for inertial microfluidic processing to tune the phenotypical composition of T‐cell products.
The CAR T cell manufacturing process is complex and expensive. In addition, the quality of the final product suffers from great variability, which is in part due to the personalized nature of the therapy. An important source of variability of final CAR T cells products is the starting cellular material for manufacture. The percentage of T-cells separated from a patient’s blood used for CAR T cell manufacture is highly variable and influenced by many factors. The percentage of ‘other’ cells typically range anywhere from 10 to 90%, and these cells interfere with the downstream T-cell modification and expansion processes, potentially preventing the production of high-quality end products. Microfluidic technologies which separate cells based on their physical attributes have previously shown great success in separating circulating cancer cells from blood but have not yet been applied in the CAR T cell manufacturing process. Early research has shown the possibility of depleting red blood cells and platelets, however little has been done in the specific purification of T-cells and depletion of other lymphocytic cells. This research therefore aimed to investigate the use of microfluidics in the separation and purification of T-cells towards addressing known bottlenecks/issues in the CAR T cells manufacturing process. We have designed and optimized microfluidic devices of various dimensions with enrichment and depletion outlets. We will report on the successful utilization of these devices in various critical steps of the manufacturing process. This abstract is also being presented as PO080. Citation Format: Mona T. Elsemary, Michelle F. Maritz, Louise Smith, Majid Warkiani, Benjamin Thierry. Microfluidic purification of T lymphocytes separated from blood for chimeric antigen receptor T-cell manufacturing [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR013.
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