A new approach to CAR T-cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21

Ptáčková, Pavlína; Musil, Jan; Štach, Martin; Lesný, Petr; Němečková, Šárka; Král, Vlastimil; Fábry, Milan; Otáhal, Pavel

doi:10.1016/j.jcyt.2017.10.001

Cited by 39 publications

(27 citation statements)

References 24 publications

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“…Besides, they also showed that addition of IL-21 to this condition further supports the enrichment and expansion of Tscm cells with an increase in the absolute numbers (20). Other studies also have shown that ex vivo supplementation with IL-21 supports development and expansion of less differentiated memory CAR T cells with superior antitumor activity (21,22). Considering the evidence that in vivo expansion of CAR T cells is correlated with the frequency of less differentiated CAR T cells within the infused products (23), it seems that ex vivo supplementation of CAR T cells with IL-21 alone or in combination with other cytokines (such as IL-7 and IL-15) has potential roles in the development and maintenance of significant fractions of less differentiated CAR T cells with superior antitumor activities.…”

Section: Ex Vivo Cell Culture Conditionsmentioning

confidence: 91%

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

et al. 2020

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CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments. CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments.

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Section: Ex Vivo Cell Culture Conditionsmentioning

confidence: 91%

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

et al. 2020

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“…Another example of a modified PB system is the "mouse codon-optimized PB transposase gene"-mPB [44]. PB systems were successfully used to generate CD19 CARs for hematological malignancies [45] as well as CARs against selected solid tumor antigens, such as CD73 [46], MSLN [47], EGFRvIII [48], and PSMA [49].…”

Section: Viral Vs Nonviral Methods Of Car T-cell Preparationmentioning

confidence: 99%

CAR T-Cell Production Using Nonviral Approaches

Lukjanov

Koutná

Šimara

2021

Journal of Immunology Research

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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.

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“…Our finite understanding of NK cells in general and their notorious aversion to transgene uptake and expression are likely to blame for the limited study of transposable elements in primary NK cells. Transposons, especially SB and PB, have been used extensively in delivering CARs to T cells for treating both hematological and solid tumors, with targets including CD19 [ 48 ], CD33 [ 49 ], CD133 [ 50 ], epidermal growth factor receptor (EGFR) [ 51 ], mesothelin [ 52 ], and glypican 3 (GPC3) [ 53 ]. Among them, a CD19-CAR and a signaling lymphocyte activation molecule family member 7 (SLAMF7)-CAR, both generated using the SB system, have already entered phase I/II clinical trial for treating leukemia or lymphoma [ 54 , 55 ] and multiple myeloma (MM) [ 56 ], respectively.…”

Section: Nk Cell Engineering With Dna Transposonsmentioning

confidence: 99%

Nonviral genome engineering of natural killer cells

et al. 2021

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Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system capable of immune surveillance. Given their ability to rapidly and effectively recognize and kill aberrant cells, especially transformed cells, NK cells represent a unique cell type to genetically engineer to improve its potential as a cell-based therapy. NK cells do not express a T cell receptor and thus do not contribute to graft-versus-host disease, nor do they induce T cell-driven cytokine storms, making them highly suited as an off-the-shelf cellular therapy. The clinical efficacy of NK cell-based therapies has been hindered by limited in vivo persistence and the immunosuppressive tumor microenvironment characteristic of many cancers. Enhancing NK cell resistance to tumor inhibitory signaling through genome engineering has the potential to improve NK cell persistence in the tumor microenvironment and restore cytotoxic functions. Alongside silencing NK cell inhibitory receptors, NK cell killing can be redirected by the integration of chimeric antigen receptors (CARs). However, NK cells are associated with technical and biological challenges not observed in T cells, typically resulting in low genome editing efficiencies. Viral vectors have achieved the greatest gene transfer efficiencies but carry concerns of random, insertional mutagenesis given the high viral titers necessary. As such, this review focuses on nonviral methods of gene transfer within the context of improving cancer immunotherapy using engineered NK cells.

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A new approach to CAR T-cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21

Cited by 39 publications

References 24 publications

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

CAR T-Cell Production Using Nonviral Approaches

Nonviral genome engineering of natural killer cells

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