Diverse expansion methods and automated platforms offer pathways to scalable CAR-T cell manufacturingNew manufacturing methods aim to scale CAR-T cell therapy production

Chimeric antigen receptor T (CAR-T) cell therapy has changed the treatment of relapsed or refractory B-cell malignancies and multiple myeloma, but manufacturing time, cost, variability, and access remain major barriers. In this critical narrative review, we position ex vivo T-cell expansion at the interface of biological signaling and engineering design and dissect how each unit operation—from selection and activation to harvest and formulation—influences the final therapeutic product. Static gas-permeable culture, rocking-motion and stirred-tank bioreactors, hollow-fiber and perfusion systems, biomaterial scaffolds, microcarriers, and defined activation nanoparticles offer distinct routes to scalable expansion. Closed automated platforms now integrate multiple unit operations, while microfluidic systems, rapid manufacturing, and process analytical technologies (PAT) create new possibilities for monitoring and control, with data-driven and AI-assisted prediction emerging as supporting tools rather than established capabilities. Expansion remains constrained by the trade-off between cell number and preservation of memory phenotype, metabolic fitness, and potency. Donor variability, raw-material quality, consumable dependence, limited interoperability, and incomplete potency assays complicate standardization. Future progress will depend on coordinated development of defined raw materials, functionally designed consumables, closed-system engineering, interoperable automation, and data-driven process control. The goal is not simply to expand more cells, but to reproducibly manufacture the right cells at an acceptable cost.