As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematologic malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for patients with cancer. In this review, we describe current CAR T cell clinical manufacturing models and discuss emerging technologic advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T cell manufacturing times and highlight regulatory challenges to scaling production for clinical use. Significance:As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development. This review provides a critical appraisal of these technologies, which can be leveraged to scale and optimize the production of nextgeneration CAR T cells. iNtRODUctiONChimeric antigen receptor (CAR)-modified T cells have emerged as an efficacious treatment for patients with certain hematologic malignancies (1). Currently, five CAR T cell products are approved for commercial use and available on the U.S. market: three for B-cell leukemia and lymphoma (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel), one for mantle cell lymphoma (brexucabtagene autoleucel), and one for multiple myeloma (idecabtagene vicleucel; refs. 2-8). These therapies involve genetically modifying patient-derived (autologous) peripheral blood T cells to express a CAR directed against antigens present on the surface of targeted tumor cells, such as the CD19 molecule, or, in the case of idecabtagene vicleucel, B-cell maturation antigen (BCMA;. After antigen recognition, the intracellular signaling domains activate the immune effector and memory functions of the CAR T cells. Once activated, these T cells proliferate, infiltrate tumor sites, secrete cytokines, and release cytolytic granules to eliminate targeted cells in an antigen-dependent manner (1). All approved CAR T cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) costimulatory signals, which are essential for eliciting a clinically relevant immune response (9-15). These CAR T cells were able to elicit complete responses (CR) in 32% to 67% of patients with lymphoma and showed better CR rates in patients with leukemia (16)(17)(18)(19).The increasing success of CAR T immunotherapies in relapsed/refractory hematologic malignancies sparked the interest of pharmaceutical companies, and several products targeting a variety of cancers are currently in the pipeline (20). However, many limitations to current CAR T cell manufacturing must be overcome before this modality can be fully integrated into routine clinical practice. First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing

The promise of stem cell (SC) therapies to restore functions of damaged tissues and organs brings enormous hope to patients, their families, loved ones, and caregivers. However, limits may exist for which indications SC therapies might be useful, efficacious, and safe. Applications of innovative therapies within regulatory boundaries and within the framework of controlled clinical trials are the norm in the scientific and medical community; such a system minimizes patient risk by setting a clear and acceptable safety and efficacy profile for new therapeutics before marketing authorization. This careful clinical validation approach often takes time, which patients suffering from terminal or debilitating diseases do not have. Not validated, unproven stem cell interventions (SCI) that promise a working treatment or cure for severe diseases have therefore found their way into the patient community, and providers of such treatments often take advantage of the public's willingness to pay large amounts of money for the misguided hope of a reliable recovery from their illnesses. We conducted a review of scientific publications, clinical case reports, and mass media publications to assess the reported cases and safety incidents associated with unproven SCI. The review also analyzes the main factors that were identified as contributing to the emergence and global rise of the “stem cell tourism” phenomenon. stem cells translational medicine 2018;1–10

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