Recent Advances in the Development of Bioreactors for Manufacturing of Adoptive Cell Immunotherapies

Abstract

Harnessing the human immune system as a foundation for therapeutic technologies capable of recognizing and killing tumor cells has been the central objective of anti-cancer immunotherapy. In recent years, there has been an increasing interest in improving the effectiveness and accessibility of this technology to make it widely applicable for adoptive cell therapies (ACTs) such as chimeric antigen receptor T (CAR-T) cells, tumor infiltrating lymphocytes (TILs), dendritic cells (DCs), natural killer (NK) cells, and many other. Automated, scalable, cost-effective, and GMP-compliant bioreactors for production of ACTs are urgently needed. The primary efforts in the field of GMP bioreactors development are focused on closed and fully automated point-of-care (POC) systems. However, their clinical and industrial application has not yet reached full potential, as there are numerous obstacles associated with delicate balancing of the complex and often unpredictable cell biology with the need for precision and full process control. Here we provide a brief overview of the existing and most advanced systems for ACT manufacturing, including cell culture bags, G-Rex flasks, and bioreactors (rocking motion, stirred-flask, stirred-tank, hollow-fiber), as well as semi- and fully-automated closed bioreactor systems.

Keywords: CAR-T; T cell; adoptive cell immunotherapy; bioreactor; point-of-care.

Figure 1

Primary types of cell cultivation systems, bioreactors, and automated systems. Cell cultivation systems are simple, require additional equipment, and involve manual cell processing at all steps. Bioreactors are more mechanized and allow certain steps to be completed in a closed aseptic mode. Semi-automated and automated systems are highly autonomous and require minimal human intervention.