EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects

Wirges, Anthea; Bunse, Mario; Joedicke, Jara J.; Blanc, Eric; Gudipati, Venugopal; Moles, Michael W.; Shiku, Hiroshi; Beule, Dieter; Huppa, Johannes B.; Höpken, Uta E.; Rehm, Armin

doi:10.1016/j.ymthe.2022.07.009

Cited by 4 publications

(5 citation statements)

References 62 publications

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“…The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) gene upregulation decreases the cytokine levels and can potentially prevent CRS onset [118]. Wirgers et al demonstrated that EBAG9 gene silencing in an animal model that received anti-CD8 CAR-T immunotherapy was not effective in the prevention of CRS [119]. The transcription suspension of cyclin-dependent kinase 7 (CDK7) inhibited the inflammatory release of cytokines and prevented CRS [120].…”

Section: Crs and Icans As Endotheliopathies: The Genetic Backgroundmentioning

confidence: 99%

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill

Evangelidis,

Kalmoukos

et al. 2024

CIMB

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Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.

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Section: Crs and Icans As Endotheliopathies: The Genetic Backgroundmentioning

confidence: 99%

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill

Evangelidis,

Kalmoukos

et al. 2024

CIMB

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“…Thus sustained signaling transducer and activation of transcriptional activator 5 (STAT5) gives anti-tumor CD4+ T cells a desirable functional profile, which is important for the optimization of CAR-T cell therapy. In addition to this, it has been shown that estrogen receptor binding fragment-associated antigen 9 (EBAG9) inhibits cytolytic enzymes released from cytotoxic T lymphocytes, while miRNA-mediated silencing of EBAG9 enhances the effector capacity of CAR-T cells in tumor models, improves tumor eradication, promotes efficient manufacturing, and reduces therapeutic dose [59], which may be a useful strategy to improve anti-tumor efficacy.…”

Section: Epigenetic Modifications In Car-t Cellsmentioning

confidence: 99%

The application of epigenetics in CAR-T therapy

Zhang¹

2023

AETR

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“…Not only enhancing expression of specific genes, but also the silencing of others may improve therapeutic properties of CAR-T cells. One example is miRNA-mediated down-regulation of expression of the EBAG9 gene (encoding the estrogen receptor-binding fragment-associated antigen 9) [ 51 ]. The CAR-T cells with silenced EBAG9 were more effective in cancer cell killing, while transcriptome profiling indicated a lack of genotoxicity or aberrant differentiation [ 51 ], confirming a good safety profile of such a construct.…”

Section: Transcriptomics In Improving the Efficacy Of Car-t Therapiesmentioning

confidence: 99%

“…One example is miRNA-mediated down-regulation of expression of the EBAG9 gene (encoding the estrogen receptor-binding fragment-associated antigen 9) [ 51 ]. The CAR-T cells with silenced EBAG9 were more effective in cancer cell killing, while transcriptome profiling indicated a lack of genotoxicity or aberrant differentiation [ 51 ], confirming a good safety profile of such a construct. Finally, comparison of transcriptomes of CAT CAR-T and FMC63 CAR-T cells indicated that the former constructs revealed enhanced activation in response to CD19 stimulation [ 52 ].…”

Section: Transcriptomics In Improving the Efficacy Of Car-t Therapiesmentioning

confidence: 99%

Transcriptomic Approaches in Studies on and Applications of Chimeric Antigen Receptor T Cells

et al. 2023

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Chimeric antigen receptor T (CAR-T) cells are specifically modified T cells which bear recombinant receptors, present at the cell surface and devoted to detect selected antigens of cancer cells, and due to the presence of transmembrane and activation domains, able to eliminate the latter ones. The use of CAR-T cells in anti-cancer therapies is a relatively novel approach, providing a powerful tool in the fight against cancer and bringing new hope for patients. However, despite huge possibilities and promising results of preclinical studies and clinical efficacy, there are various drawbacks to this therapy, including toxicity, possible relapses, restrictions to specific kinds of cancers, and others. Studies desiring to overcome these problems include various modern and advanced methods. One of them is transcriptomics, a set of techniques that analyze the abundance of all RNA transcripts present in the cell at certain moment and under certain conditions. The use of this method gives a global picture of the efficiency of expression of all genes, thus revealing the physiological state and regulatory processes occurring in the investigated cells. In this review, we summarize and discuss the use of transcriptomics in studies on and applications of CAR-T cells, especially in approaches focused on improved efficacy, reduced toxicity, new target cancers (like solid tumors), monitoring the treatment efficacy, developing novel analytical methods, and others.

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EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects

Cited by 4 publications

References 62 publications

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill

The application of epigenetics in CAR-T therapy

Transcriptomic Approaches in Studies on and Applications of Chimeric Antigen Receptor T Cells

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