Transposon-mediated generation of CAR-T cells shows efficient anti B-cell leukemia response after ex vivo expansion

Chicaybam, Leonardo; Abdo, Luiza; Viegas, Mariana; Marques, Luisa Vieira Codeço; Sousa, Priscila de; Batista-Silva, Leonardo Ribeiro; Alves-Monteiro, Viviane; Bonecker, Simone; Monte-Mór, Bárbara; Bonamino, Martin H.

doi:10.1038/s41434-020-0121-4

Cited by 31 publications

(25 citation statements)

References 35 publications

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“…Cells 2020, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/cells and CD4+ subpopulations, thus representing a favorable phenotype to ensure a persistent antitumor effect [57]. Generation of CAR T-cells under a point-of-care approach will allow a more rapid (<2 days) manufacture in absence of ex vivo activation and expansion, further widening the perspectives of simplified, cost effective and more accessible CAR T-cell therapy [58,59].…”

Section: Car T-cells Engineered With Sleeping Beauty Transposon Vectorsmentioning

confidence: 99%

“…The resulting cell populations were assayed at the end of the 8-day culture period and were shown to elicit robust antileukemic activity both in vitro and in vivo. The majority of CAR T-cells had a central memory (CM) (CD45RO−CD62L+) phenotype, in both CD8+ and CD4+ subpopulations, thus representing a favorable phenotype to ensure a persistent antitumor effect [ 57 ]. Generation of CAR T-cells under a point-of-care approach will allow a more rapid (<2 days) manufacture in absence of ex vivo activation and expansion, further widening the perspectives of simplified, cost effective and more accessible CAR T-cell therapy [ 58 , 59 ].…”

Section: Preclinical Evolution Of Sleeping Beauty Vector Designmentioning

confidence: 99%

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Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

Magnani

Tettamanti

Alberti

et al. 2020

Cells

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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.

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Section: Car T-cells Engineered With Sleeping Beauty Transposon Vectorsmentioning

confidence: 99%

Section: Preclinical Evolution Of Sleeping Beauty Vector Designmentioning

confidence: 99%

Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

Magnani

Tettamanti

Alberti

et al. 2020

Cells

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“…47 Assuming 50% viability and 10% transfection efficiency, by processing around 3 × 10 9 PBMCs it would be possible to generate 15 × 10 7 CAR+ T cells, equivalent to 2.1 × 10 6 CAR+ T cells/kg for a 70 kg patient. These numbers are enough as a starting point for short CAR-T expansion protocols, such as the approach recently described by our group 48 and represent realistic start points for POC-based protocols. Therefore, production of CAR-T cells for POC approach using currently available devices is potentially feasible and compatible with T cell doses used in the clinical practice.…”

Section: Comparison Of Anti-tumor Activity Of Cells 4 H Vs or 24 H Pomentioning

confidence: 99%

Development of CAR-T cell therapy for B-ALL using a point-of-care approach

et al. 2020

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Recently approved by the FDA and European Medicines Agency, CART cell therapy is a new treatment option for B-cell malignancies. Currently, CART cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs, and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CART cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CART cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CART cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 h of gene transfer. In an effort to better characterize the infused CART cells, we show that 19BBz T lymphocytes infused after 24 h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggest that POC approach is a viable alternative for the generation and use of CART cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries.

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“…Another limitation is the need of large-scale production of viral vectors and associated quality control performed by highly competent technicians [28,128]. To surpass these bottlenecks, non-viral technologies, including Sleeping Beauty and PiggyBac transposon-based vectors [129,130], pDNA transfection [131,132], or different nanoformulations (reviewed in [35]), are being pursued.…”

Section: Car-t Cells Therapymentioning

confidence: 99%

Gene Therapy in Cancer Treatment: Why Go Nano?

et al. 2020

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The proposal of gene therapy to tackle cancer development has been instrumental for the development of novel approaches and strategies to fight this disease, but the efficacy of the proposed strategies has still fallen short of delivering the full potential of gene therapy in the clinic. Despite the plethora of gene modulation approaches, e.g., gene silencing, antisense therapy, RNA interference, gene and genome editing, finding a way to efficiently deliver these effectors to the desired cell and tissue has been a challenge. Nanomedicine has put forward several innovative platforms to overcome this obstacle. Most of these platforms rely on the application of nanoscale structures, with particular focus on nanoparticles. Herein, we review the current trends on the use of nanoparticles designed for cancer gene therapy, including inorganic, organic, or biological (e.g., exosomes) variants, in clinical development and their progress towards clinical applications.

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Transposon-mediated generation of CAR-T cells shows efficient anti B-cell leukemia response after ex vivo expansion

Cited by 31 publications

References 35 publications

Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

Development of CAR-T cell therapy for B-ALL using a point-of-care approach

Gene Therapy in Cancer Treatment: Why Go Nano?

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