Inducible secretion of IL-21 augments anti-tumor activity of piggyBac-manufactured chimeric antigen receptor T cells

Štach, Martin; Ptáčková, Pavlína; Mucha, Martin; Musil, Jan; Klener, P; Otáhal, Pavel

doi:10.1016/j.jcyt.2020.08.005

Cited by 39 publications

(26 citation statements)

References 22 publications

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“…Another small patient cohort study also showed that responders had a lower percentage of senescent T cells in the apheresis product prior to the CAR T cell manufacturing process [81] . Moreover, according to preclinical experiments, enhancing proliferative and cytotoxic capacities and preventing the terminal differentiation of T cells by CD27 or CD28 transduction [82 , 83] or gamma chain cytokine treatment [84 , 85] may help restore antitumour activity. These data indicate that fewer senescent T cells may be more therapeutically effective.…”

Section: Potential Prognostic Biomarkers In Cancer Treatmentmentioning

confidence: 99%

“…The gamma chain cytokines, IL-2, IL-7, IL-15, and IL-21 serve as critical regulators of the survival and homeostasis of T cells [ 84 , 85 , 88 , 89 ]. Increasing evidence indicates that gamma chain cytokine-fuel cancer immunotherapy is associated with delayed or reversed senescence in antigen-specific CD8 + T or CAR T cells [ 84 , 85 , 88 , 89 ]. For example, IL-7 but not IL-2, or IL-15 inhibits tumour-induced T cell senescence by maintaining CD27/CD28 expression and proliferative capacity and reducing their suppressive function [88] .…”

Section: Senescent T Cells As Therapeutic Targetsmentioning

confidence: 99%

“…For example, IL-7 but not IL-2, or IL-15 inhibits tumour-induced T cell senescence by maintaining CD27/CD28 expression and proliferative capacity and reducing their suppressive function [88] . IL-15 and IL-21 prevent the terminal differentiation of tumour antigen-specific T cells and promote their expansion and effector functions [ 84 , 85 , 89 ]. The IL-15 super-agonist complex ALT-803 can also upregulate the expression of NKG2D and exhibit nonspecific cytotoxicity against tumour cells [90] .…”

Section: Senescent T Cells As Therapeutic Targetsmentioning

confidence: 99%

See 2 more Smart Citations

Senescent T cells: a potential biomarker and target for cancer therapy

Zhang

Xue

et al. 2021

EBioMedicine

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The failure of T cells to eradicate tumour cells in the tumour microenvironment is mainly due to the dysfunction of T cells. Senescent T cells, with defects in proliferation and effector functions, accumulate in ageing, chronic viral infections, and autoimmune disorders where antigen stimulation persists. Increasing evidence suggests that inducing T cell senescence is a key strategy used by malignant tumours to evade immune surveillance. In this review, we summarize the general features, functional regulation, and signalling network of senescent T cells in tumour development and highlight their potential as prognostic biomarkers in multiple cancer treatments, including chemotherapy, radiotherapy, and immunotherapy. Moreover, we discuss possible therapeutic strategies for preventing or rejuvenating senescence in tumour-specific T cells. Understanding these critical issues may provide novel strategies to enhance cancer immunotherapy.

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Section: Potential Prognostic Biomarkers In Cancer Treatmentmentioning

confidence: 99%

Section: Senescent T Cells As Therapeutic Targetsmentioning

confidence: 99%

Section: Senescent T Cells As Therapeutic Targetsmentioning

confidence: 99%

See 1 more Smart Citation

Senescent T cells: a potential biomarker and target for cancer therapy

Zhang

Xue

et al. 2021

EBioMedicine

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“…However, transposon systems represent a viable alternative to mediate gene transfer, and have been continuously tested in preclinical CAR-T cell therapy settings. SB pioneered applications with the well-characterized CD19-specific CAR-T cells (reviewed in [ 24 , 206 ]), and was joined by PB [ 206 , 207 , 208 ] and Tol2 [ 113 ] to demonstrate suppression of B cell lymphoma progression both in vitro and in vivo. The most recent developments include CAR-T cell engineering for alternative targets such as the granulocyte-macrophage colony-stimulating factor receptor (hGMR or CD116) for hematological malignancies [ 209 ], the epidermal growth factor receptor (EGFR) as a target for non-small-cell lung carcinoma [ 210 ], glypican-3 and EGFRvIII targeting hepatocellular carcinoma [ 211 , 212 ] and membrane-proximal mesothelin (MSLN) epitope-targeting against MSLN-positive solid tumors [ 213 ].…”

Section: Preclinical Applicationsmentioning

confidence: 99%

Contemporary Transposon Tools: A Review and Guide through Mechanisms and Applications of Sleeping Beauty, piggyBac and Tol2 for Genome Engineering

Sandoval-Villegas

Nurieva

Amberger

et al. 2021

IJMS

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Transposons are mobile genetic elements evolved to execute highly efficient integration of their genes into the genomes of their host cells. These natural DNA transfer vehicles have been harnessed as experimental tools for stably introducing a wide variety of foreign DNA sequences, including selectable marker genes, reporters, shRNA expression cassettes, mutagenic gene trap cassettes, and therapeutic gene constructs into the genomes of target cells in a regulated and highly efficient manner. Given that transposon components are typically supplied as naked nucleic acids (DNA and RNA) or recombinant protein, their use is simple, safe, and economically competitive. Thus, transposons enable several avenues for genome manipulations in vertebrates, including transgenesis for the generation of transgenic cells in tissue culture comprising the generation of pluripotent stem cells, the production of germline-transgenic animals for basic and applied research, forward genetic screens for functional gene annotation in model species and therapy of genetic disorders in humans. This review describes the molecular mechanisms involved in transposition reactions of the three most widely used transposon systems currently available (Sleeping Beauty, piggyBac, and Tol2), and discusses the various parameters and considerations pertinent to their experimental use, highlighting the state-of-the-art in transposon technology in diverse genetic applications.

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“…ŠTach, M et al. ( 86 ) constructed gene-edited IL-21 CAR-T cells targeting CD19, and studied the effect of IL-21 on its function. The results showed that IL-21 enhanced the expansion of CAR-T cells, and prevented the differentiation of CAR-T cells into late memory phenotype.…”

Section: Correlation Study Of Gene-edited Interleukin Car-t Cells In the Treatment Of Malignant Tumorsmentioning

confidence: 99%

Gene-Edited Interleukin CAR-T Cells Therapy in the Treatment of Malignancies: Present and Future

et al. 2021

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In recent years, chimeric antigen receptor T cells (CAR-T cells) have been faced with the problems of weak proliferation and poor persistence in the treatment of some malignancies. Researchers have been trying to perfect the function of CAR-T by genetically modifying its structure. In addition to the participation of T cell receptor (TCR) and costimulatory signals, immune cytokines also exert a decisive role in the activation and proliferation of T cells. Therefore, genetic engineering strategies were used to generate cytokines to enhance tumor killing function of CAR-T cells. When CAR-T cells are in contact with target tumor tissue, the proliferation ability and persistence of T cells can be improved by structurally or inductively releasing immunoregulatory molecules to the tumor region. There are a large number of CAR-T cells studies on gene-edited cytokines, and the most common cytokines involved are interleukins (IL-7, IL-12, IL-15, IL-18, IL-21, IL-23). Methods for the construction of gene-edited interleukin CAR-T cells include co-expression of single interleukin, two interleukin, interleukin combined with other cytokines, interleukin receptors, interleukin subunits, and fusion inverted cytokine receptors (ICR). Preclinical and clinical trials have yielded positive results, and many more are under way. By reading a large number of literatures, we summarized the functional characteristics of some members of the interleukin family related to tumor immunotherapy, and described the research status of gene-edited interleukin CAR-T cells in the treatment of malignant tumors. The objective is to explore the optimized strategy of gene edited interleukin-CAR-T cell function.

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Inducible secretion of IL-21 augments anti-tumor activity of piggyBac-manufactured chimeric antigen receptor T cells

Cited by 39 publications

References 22 publications

Senescent T cells: a potential biomarker and target for cancer therapy

Senescent T cells: a potential biomarker and target for cancer therapy

Contemporary Transposon Tools: A Review and Guide through Mechanisms and Applications of Sleeping Beauty, piggyBac and Tol2 for Genome Engineering

Gene-Edited Interleukin CAR-T Cells Therapy in the Treatment of Malignancies: Present and Future

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