Regenerative Medicine Manufacturing.

Abstract

This is an exciting time for regenerative medicine as cell-based therapies are advancing to the clinic at a rapid pace. 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 successes with adoptive T-cell therapy, including CAR-T cells, suggest the potential of these cells to revolutionize cancer treatment. Gomes-Silva and Ramos1 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 of moving to allogeneic “universal” T cells. Piscopo et al.2 describe the current CAR-T cell manufacturing process from harvesting and transporting the patient's cells, activating and expanding the cells, genetic modification, and quality control and assurance. The authors have identified areas in which 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.3 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.4 compared growth kinetics of bone marrow MSCs isolated from 10 different donors of similar age and found an approximately two-fold variation in cell yield over 3 passages, suggesting a window of process operation. Gupta et al.5 developed an integrated process for expanding human periosteum-derived stem cells (hPDCs) and priming them for chondrogenic differentiation. hPDCs were cultured to confluence on microcarriers in a spinner flask then treated with TGF-β to form macrotissues that demonstrated chondrogenic properties when implanted in vivo. While mimicking in vivo microenvironments has often been an effective strategy to control stem cell fates in vitro, the complexity of these microenvironments complicates manufacturing processes. Methods to identify the key drivers of cell fate are needed. Richardson et al.6 describe a 3D alginate array that enables combinatorial screening of substrate chemical and physical properties. They utilized this platform to identify relationships between cell aggregation state and scaffold properties during encapsulated human embryonic stem cell self-renewal and differentiation to pancreatic cells. Such high-throughput screening platforms will be valuable tools in designing robust and scalable stem cell manufacturing processes. Stem cells can also provide in vitro models to understand disease and identify novel treatments. Stebbins et al.7 describe the use of human induced pluripotent stem cells (iPSCs) in modeling the blood-brain barrier (BBB). They identified specific retinoic acid agonists that impart tight barrier function in iPSC-derived brain microvascular endothelial cells. These agonists can be used to improve the process for manufacturing a BBB model for drug screening and delivery applications, and their findings suggest specific retinoic acid receptor targets to mitigate BBB dysfunction. To realize the tremendous potential indicated by research and early clinical trials on therapeutic cells we will need to develop innovative new manufacturing platforms, as indicated by the reviews and research articles in this special issue. The bioengineering community will be instrumental in the success of the regenerative medicine field and we look forward to watching this field flourish. Prof. Joaquim M.S. Cabral Universidade de Lisboa, Lisboa, Portugal, E-mail: [email protected] Prof. Sean P. Palecek University of Wisconsin, Madison, WI, USA, E-mail: [email protected]