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Regenerative Medicine Manufacturing

This is an exciting time for regenerative medicine as cell-based therapies are advancing to theclinic at a rapidpace.For example, in 2017 the US Food and Drug Administration approved chimeric antigen receptor (CAR)-T cell therapies for the treatment of children with acute lymphoblastic leukemia and adults with advanced lymphoma. There are thousands of clinical trials underway exploring the use of adult stem cells, including hematopoietic and mesenchymal stem cells, to treat disease such as cancers, auto-immune disorders, immunodeficiency, heart failure, neurological disease, metabolic disorders, and genetic diseases. Clinical trials are also underway or in planning phases to use cells derived from human pluripotent stem cells to treat diseases including spinal cord injury, neurodegenerative disorders, blindness and other eye disease, diabetes, and heart disease. Success of these cellular therapies in the clinic will require the ability to manufacture a safe and effective product at the scale needed to replace damaged tissue. While the biotechnology industry has cultured vast quantities of mammalian cells to produce protein products for decades, there are unique challenges associated with a living cell product. This Special issue of Biotechnology Journal is devoted to addressing the state-of-the-art in manufacturing cellular products for regenerative applications. Recent clinical successeswith adoptive T-cell therapy, including CAR-T cells, suggest the potential of these cells to revolutionize cancer treatment. Gomes-Silva and Ramos provide an overview of CARs and CAR optimization to effectively target specific tumor types. They describe current CAR-T autologous manufacturing processes and illustrate the cost benefits and technical challenges ofmoving to allogeneic “universal”Tcells. Piscopoet al. describe the current CAR-T cell manufacturing process from harvesting and transporting the patient’s cells, activating and expanding the cells, geneticmodification, and quality control and assurance. The authors have identified areas inwhich bioengineering approaches will improve produce CAR-T cell safety, efficacy, and accessibility via genome editing, advanced biomaterials, tissue engineering of in vitro models, and manufacturing process design and control. Significant advances have been made recently in expanding and controlling the differentiation fates of stem cells. Hematopoietic cell transplantation has been used to treat patients with blood cancers and immunological disorders for over 60 years. However, challenges in ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs) limit the clinical efficacy of these cells. Costa et al. reviewed recent advances in expanding and improving the function of HSPCs by incorporating key components of the adult bone marrow niche, including soluble factors, immobilized cues, and stromal cell co-culture, in manufacturing processes. Similarly, human mesenchymal stem/stromal cells (MSCs) suffer a loss of potency during expansion ex vivo and donor-to-donor variability in expansion capacity. Detela et al. compared growth kinetics of bone