Abstract
Chimeric Antigen Receptor (CAR) T-cell therapy has become a new therapeutic reality for refractory and relapsed leukemia patients and is also emerging as a potential therapeutic option in solid tumors. Viral vector-based CAR T-cells initially drove these successful efforts; however, high costs and cumbersome manufacturing processes have limited the widespread clinical implementation of CAR T-cell therapy. Here we will discuss the state of the art of the transposon-based gene transfer and its application in CAR T immunotherapy, specifically focusing on the Sleeping Beauty (SB) transposon system, as a valid cost-effective and safe option as compared to the viral vector-based systems. A general overview of SB transposon system applications will be provided, with an update of major developments, current clinical trials achievements and future perspectives exploiting SB for CAR T-cell engineering. After the first clinical successes achieved in the context of B-cell neoplasms, we are now facing a new era and it is paramount to advance gene transfer technology to fully exploit the potential of CAR T-cells towards next-generation immunotherapy.
Highlights
Background on Chimeric Antigen Receptor (CAR) TCell Therapy in Acute LeukemiasGene Transfer Strategies, ClinicalSettings and AccessibilityThe concept that in allogeneic hematopoietic transplantation the immune system plays a relevant role in the control of leukemic disease is supported by the clinical observation that immunological effector mechanisms are partly responsible for the elimination of leukemic blasts.it is well known that the efficacy of allo-HSCT depends on the anti-leukemic alloreactivity of the donor-derived T-cells, defined as the graft-versus-leukemia (GvL) effect
In this review we will discuss the employment of a non-viral Sleeping Beauty transposon-based CAR-gene transfer approach, which is overall associated with less cumbersome protocols and reduces the cost of goods, as a unique alternative to current viral-based strategies
PiggyBac has become, together with Sleeping Beauty (SB) transposon, one of the most exploited non-viral gene transfer systems [31]. Both the SB and piggyBac transposon systems consist of two components: The engineered transposon, which carries the gene of interest to be inserted into the genome flanked by inverted terminal repeats (ITRs), and the transposase, which catalyzes the process of “cut-and-paste” transposition
Summary
The concept that in allogeneic hematopoietic transplantation (allo-HSCT) the immune system plays a relevant role in the control of leukemic disease is supported by the clinical observation that immunological effector mechanisms are partly responsible for the elimination of leukemic blasts. While lentiviral vectors display those appealing features, the lack of widely available stable vector packaging systems, limitations in the lot size and lot-to-lot variability due to the required multi-plasmid transient transfection procedure [23] make their accessibility complicated and expensive [24,25] For these reasons, researchers are looking for more affordable gene transfer methods able to combine the favorable attributes of integrating viral vectors (i.e., efficiency in genomic insertion) whilst eliminating or at the least significantly reducing the inadvertent side-effects (i.e., insertional oncogenesis). In this review we will discuss the employment of a non-viral Sleeping Beauty transposon-based CAR-gene transfer approach, which is overall associated with less cumbersome protocols and reduces the cost of goods, as a unique alternative to current viral-based strategies
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