Ex vivo expansion of T lymphocytes is a central process in the generation of cellular therapies targeted at tumors and other disease-relevant structures, which currently cannot be reached by established pharmaceuticals. The influence of culture conditions on T cell functions is, however, incompletely understood. In clinical applications of ex vivo expanded T cells, so far, a relatively classical standard cell culture methodology has been established. The expanded cells have been characterized in both preclinical models and clinical studies mainly using a therapeutic endpoint, for example antitumor response and cytotoxic function against cellular targets, whereas the influence of manipulations of T cells ex vivo including transduction and culture expansion has been studied to a much lesser detail, or in many contexts remains unknown. This includes the circulation behavior of expanded T cells after intravenous application, their intracellular metabolism and signal transduction, and their cytoskeletal (re)organization or their adhesion, migration, and subsequent intra-tissue differentiation. This review aims to provide an overview of established T cell expansion methodologies and address unanswered questions relating in vivo interaction of ex vivo expanded T cells for cellular therapy.
Ex vivo expansion is a necessary process in the current CAR T cell manufacturing protocols. Different ex vivo expansion conditions and duration of expansion are under investigation to enhance functionality and longer persistence of CAR T cell products upon infusion. Recent studies have revealed that shorter culture periods lead to a higher percentage of less differentiated stem-like memory T cells (Tscm) and central memory T cells (Tcm) in the final product. Multiple clinical trials with short and rapid manufacturing protocols (with 3 days of manufacturing) for CAR T cells are underway. However, the changes induced in the T cells during ex vivo manufacturing conditions and their impact on the functionality of CAR T cells upon infusion are not deeply understood.
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