Abstract
Chimeric antigen receptor T-cells (CAR T-cells) represent a novel and promising approach in cancer immunotherapy. According to the World Health Organization (WHO), the number of oncological patients is steadily growing in developed countries despite immense progress in oncological treatments, and the prognosis of individual patients is still relatively poor. Exceptional results have been recorded for CAR T-cell therapy in patients suffering from B-cell malignancies. This success opens up the possibility of using the same approach for other types of cancers. To date, the most common method for CAR T-cell generation is the use of viral vectors. However, dealing with virus-derived vectors brings possible obstacles in the CAR T-cell manufacturing process owing to strict regulations and high cost demands. Alternative approaches may facilitate further development and the transfer of the method to clinical practice. The most promising substitutes for virus-derived vectors are transposon-derived vectors, most commonly sleeping beauty, which offer great coding capability and a safe integration profile while maintaining a relatively low production cost. This review is aimed at summarizing the state of the art of nonviral approaches in CAR T-cell generation, with a unique perspective on the conditions in clinical applications and current Good Manufacturing Practice. If CAR T-cell therapy is to be routinely used in medical practice, the manufacturing cost and complexity need to be as low as possible, and transposon-based vectors seem to meet these criteria better than viral-based vectors.
Highlights
In 1989, Zelig Eshar [1] and his team published the proof of concept of chimeric antigen receptors (CARs) T-cell therapy: first, T-cells were generated that expressed chimeric receptors that were activated after contact with target cells bearing the corresponding antibody
The most important CAR T-cell clinical trial was performed in 2011 by Carl June’s research group [2, 3]. They used a CAR against Bcell antigen CD19 to treat chronic lymphoid leukemia (CLL) in 3 patients
Kymriah (Novartis) and Yescarta (Gilead-KitePharma) were both approved by the Food and Drug Administration (FDA) for the treatment of B-cell-related malignancies
Summary
The sleeping beauty (SB) transposon system is currently being used as a substitute for viral-based vectors in the preparation of, for example, CD19+ CAR T-cells [23], with reported antitumor activity both in vitro and in vivo [24]. Higher transposition activity in various mammalian cells positions the PB transposon at the top of potential nonviral vectors for human cell transgenesis and the manufacture of CAR T-cells. Another essential ability of the vector is the size of the cargo capacity. Aside from electroporation, the usage of lipid nanoparticles as a form of mRNA transport was recently demonstrated in the preparation of CAR T-cells [57] Unlike electroporation, this method is significantly less toxic to the transduced cells. Both approaches are suitable for cGMP-quality CAR T-cell production, electroporation is being used far more frequently
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