<i>Sleeping Beauty</i>transposition: from biology to applications

Narayanavari, Suneel A.; Chilkunda, Shreevathsa S; Ivics, Zoltán; Izsvák, Zsuzsanna

doi:10.1080/10409238.2016.1237935

Cited by 45 publications

(31 citation statements)

References 228 publications

(310 reference statements)

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“…In 1997, Ivics et al reconstructed “Sleeping Beauty” (SB) transposon system using bioinformatic methods [13]. As the first synthetic DNA transposon, it is asserted that SB transposon can be inserted into genome randomly and ensures long-term stable expression of objective genes [14]. Huang et al reported for the first time using SB transposon technology to manufacture CD19 CAR-T cells, and confirmed the specific killing ability targeting CD19-positive leukemia and lymphoma cells [15].…”

Section: Manufacture Technologiesmentioning

confidence: 99%

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

et al. 2017

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Refractory/relapsed B-cell acute lymphoblastic leukemia remains to be a significant cause of cancer-associated morbidity and mortality for children and adults. Developing novel and effective molecular-targeted approaches is thus a major priority. Chimeric antigen receptor-modified T cell (CAR-T) therapy, as one of the most promising targeted immunotherapies, has drawn extensive attention and resulted in multiple applications. According to published studies, CD19-directed CAR-T cells (CD19 CAR-T) can reach a complete remission rate of 94% in both children and adults with refractory/relapsed ALL, much higher than that of chemotherapy. However, the encouraging outcomes are often associated with complications such as cytokine release syndrome (CRS), serious neurotoxicity, and on-target off-tumor effect, which seriously impeded further clinical application of CAR-T cells. Moreover, CAR-T therapy is typically associated with high relapse rate. This article briefly reviews the manufacture technologies, the conditioning regimens, the cell infusion doses, as well as the prevention and treatment strategies of complications for CAR-T cell therapy.

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Section: Manufacture Technologiesmentioning

confidence: 99%

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

et al. 2017

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“…SB has proven successful as a therapeutic vector in various preclinical studies demonstrating long-term gene expression in a wide range of tissues and primary cells. 37 Moreover, SB technology reached clinical level as the first phase I clinical trials using SB transposons have recently been conducted, albeit in an ex vivo gene therapy setting. 38 To transfer the SB transposon-mediated approach described in this preclinical study from bench to clinical setting, the issue of hydrodynamics-based delivery and safety must be addressed.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy

Verhenne

Vandeputte

Pareyn

et al. 2017

ATVB

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“…The Sleeping Beauty (SB) transposon system [1] has been developed as a useful and promising tool for genetic engineering, including gene therapies (recently reviewed in [2][3][4][5][6][7]). The major advantage of SB gene delivery is that it combines the favorable features of viral vectors with those of naked DNA molecules, namely i) permanent insertion of transgene constructs into the genome by the transposition mechanism leads to sustained (potentially life-long) and efficient transgene expression in preclinical animal models (recently reviewed in [4][5][6]); ii) transposon vectors can be maintained and propagated as plasmid DNA, which makes vector manufacture scalable and cost-effective, and only requires S1 biological safety conditions, thereby significantly simplifying manufacture of the cell-based product.…”

Section: Sleeping Beauty Transposon System For Nonviral Engineering Omentioning

confidence: 99%

Genomic Analyses of SLAMF7 CAR-T Cells Manufactured by Sleeping Beauty Transposon Gene Transfer for Immunotherapy of Multiple Myeloma

Miskey

Amberger

Reiser

et al. 2019

Preprint

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Widespread treatment of human diseases with gene therapies necessitates the development of gene transfer vectors that integrate genetic information effectively, safely and economically. Accordingly, significant efforts have been devoted to engineer novel tools that i) achieve high-level stable gene transfer at low toxicity to the host cell; ii) induce low levels of genotoxicity and possess a ‘safe’ integration profile with a high proportion of integrations into safe genomic locations; and iii) are associated with acceptable cost per treatment and scalable/exportable vector production to serve large numbers of patients. The Sleeping Beauty (SB) transposon has been transformed into a vector system that is fulfilling these requirements.In the CARAMBA project, we use SB transposition to genetically modify T cells with a chimeric antigen receptor (CAR) specific for the SLAMF7 antigen, that is uniformly and highly expressed on malignant plasma cells in multiple myeloma. We have demonstrated that SLAMF7 CAR-T cells confer specific and very potent anti-myeloma reactivity in pre-clinical models, and are therefore preparing a Phase I/IIa clinical trial of adoptive immunotherapy with autologous, patient-derived SLAMF7-CAR T cells in multiple myeloma (EudraCT Nr. 2019-001264-30/CARAMBA-1).Here we report on the characterization of genomic safety attributes in SLAMF7 CAR-T cells that we prepared in three clinical-grade manufacturing campaigns under good manufacturing practice (GMP), using T cells that we obtained from three healthy donor volunteers. In the SLAMF7 CAR-T cell product, we determined the average transposon copy number, the genomic insertion profile, and presence of residual SB100X transposase. The data show that the SLAMF7 CAR transposon had been inserted into the T cell genome with the close-to-random distribution pattern that is typical for SB, and with an average transposon copy number ranging between 6 and 12 per T cell. No residual SB100X transposase could be detected by Western blotting in the infusion products. With these attributes, the SLAMF7 CAR-T products satisfy criteria set forth by competent regulatory authorities in order to justify administration of SLAMF7 CAR-T cells to humans in the context of a clinical trial. These data set the stage for the CARAMBA clinical trial, that will be the first in the European Union to use virus-free SB transposition for CAR-T engineering.DisclosuresThis project is receiving funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 754658 (CARAMBA).

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Sleeping Beautytransposition: from biology to applications

Cited by 45 publications

References 228 publications

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy

Genomic Analyses of SLAMF7 CAR-T Cells Manufactured by Sleeping Beauty Transposon Gene Transfer for Immunotherapy of Multiple Myeloma

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