Industrializing Autologous Adoptive Immunotherapies: Manufacturing Advances and Challenges

Abstract

Cell therapy has proven to be a burgeoning field of investigation, evidenced by hundreds of clinical trials being conducted worldwide across a variety of cell types and indications. Many cell therapies have been shown to be efficacious in humans, such as modified T-cells and natural killer (NK) cells. Adoptive immunotherapy has shown the most promise in recent years, with particular emphasis on autologous cell sources. Chimeric Antigen Receptor (CAR)-based T-cell therapy targeting CD19-expressing B-cell leukemias has shown remarkable efficacy and reproducibility in numerous clinical trials. Recent marketing approval of Novartis' Kymriah™ (tisagenlecleucel) and Gilead/Kite's Yescarta™ (axicabtagene ciloleucel) by the FDA further underscores both the promise and legwork to be done if manufacturing processes are to become widely accessible. Further work is needed to standardize, automate, close, and scale production to bring down costs and democratize these and other cell therapies. Given the multiple processing steps involved, commercial-scale manufacturing of these therapies necessitates tighter control over process parameters. This focused review highlights some of the most recent advances used in the manufacturing of therapeutic immune cells, with a focus on T-cells. We summarize key unit operations and pain points around current manufacturing solutions. We also review emerging technologies, approaches and reagents used in cell isolation, activation, transduction, expansion, in-process analytics, harvest, cryopreservation and thaw, and conclude with a forward-look at future directions in the manufacture of adoptive immunotherapies.

Keywords: CAR T-cells; NK cell; autologous; bioreactor; cellular therapy; chimeric antigen receptor; immunotherapy manufacturing; scale-out.

Figure 1

Generic patient specific adoptive immunotherapy workflow. Donor leukophoresis sample undergoes selection to enrich for the cell of interest (e.g., T-cells, NK cells). Previously manufactured viral vector is added to genetically modify the immune cells, conferring new cancer recognition receptors. The modified cells are then expanded to therapeutically relevant numbers, followed by washing, formulation, bagging, and cryostorage into an infusible patient dose. The cell product is shipped to the clinical site where it is thawed and administered to the patient.