Advances in manufacturing chimeric antigen receptor immune cell therapies

Abstract

Biomedical research has witnessed significant strides in manufacturing chimeric antigen receptor T cell (CAR-T) therapies, marking a transformative era in cellular immunotherapy. Nevertheless, existing manufacturing methods for autologous cell therapies still pose several challenges related to cost, immune cell source, safety risks, and scalability. These challenges have motivated recent efforts to optimize process development and manufacturing for cell therapies using automated closed-system bioreactors and models created using artificial intelligence. Simultaneously, non-viral gene transfer methods like mRNA, CRISPR genome editing, and transposons are being applied to engineer T cells and other immune cells like macrophages and natural killer cells. Alternative sources of primary immune cells and stem cells are being developed to generate universal, allogeneic therapies, signaling a shift away from the current autologous paradigm. These multifaceted innovations in manufacturing underscore a collective effort to propel this therapeutic approach toward broader clinical adoption and improved patient outcomes in the evolving landscape of cancer treatment. Here, we review current CAR immune cell manufacturing strategies and highlight recent advancements in cell therapy scale-up, automation, process development, and engineering.

Keywords: Adoptive T cell therapy; Artificial Intelligence; Automation; Biomanufacturing; CRISPR; Genome editing.

Fig. 1

Current CAR immune cell manufacturing process versus potential future CAR immune cell manufacturing process. Current CAR immune cell manufacturing processes require multi-stage processes, cryopreservation, and transportation from the clinic to centralized manufacturing facilities and back to the clinic. This process involves multiple human contact points (numbered), defined as points in the process in which human intervention is necessary to manufacture CAR immune cells, leading to issues like contamination, variability, and cell loss. Future cell therapy manufacturing processes have the potential to minimize human contact points (numbered) and eliminate the need for cryopreservation or transportation of cells. Automation in existing manufacturing processes already facilitates isolation, activation, delivery of the CAR, and expansion of CAR immune cells, thereby reducing variability and contamination. Anticipated advancements in this field involve the integration of artificial intelligence (AI), using data from previous clinical trials and manufacturing workflows like patient response, dose, tumor burden and side effects such as cytokine release storms. These advances would allow for dynamic optimization of CAR immune cell manufacturing through proactive and reactive real-time changes