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EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells

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EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells. / Kailayangiri, Sareetha; Altvater, Bianca; Lesch, Stefanie; Balbach, Sebastian; Göttlich, Claudia; Kühnemundt, Johanna; Mikesch, Jan-Henrik; Schelhaas, Sonja; Jamitzky, Silke; Meltzer, Jutta; Farwick, Nicole; Greune, Lea; Fluegge, Maike; Kerl, Kornelius; Lode, Holger N; Siebert, Nikolai; Müller, Ingo; Walles, Heike; Hartmann, Wolfgang; Rossig, Claudia.

in: MOL THER, Jahrgang 27, Nr. 5, 08.05.2019, S. 933-946.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Kailayangiri, S, Altvater, B, Lesch, S, Balbach, S, Göttlich, C, Kühnemundt, J, Mikesch, J-H, Schelhaas, S, Jamitzky, S, Meltzer, J, Farwick, N, Greune, L, Fluegge, M, Kerl, K, Lode, HN, Siebert, N, Müller, I, Walles, H, Hartmann, W & Rossig, C 2019, 'EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells', MOL THER, Jg. 27, Nr. 5, S. 933-946. https://doi.org/10.1016/j.ymthe.2019.02.014

APA

Kailayangiri, S., Altvater, B., Lesch, S., Balbach, S., Göttlich, C., Kühnemundt, J., Mikesch, J-H., Schelhaas, S., Jamitzky, S., Meltzer, J., Farwick, N., Greune, L., Fluegge, M., Kerl, K., Lode, H. N., Siebert, N., Müller, I., Walles, H., Hartmann, W., & Rossig, C. (2019). EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells. MOL THER, 27(5), 933-946. https://doi.org/10.1016/j.ymthe.2019.02.014

Vancouver

Kailayangiri S, Altvater B, Lesch S, Balbach S, Göttlich C, Kühnemundt J et al. EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells. MOL THER. 2019 Mai 8;27(5):933-946. https://doi.org/10.1016/j.ymthe.2019.02.014

Bibtex

@article{8199cc337980427786ecdebdbb1ee1d7,
title = "EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells",
abstract = "Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.",
keywords = "Journal Article",
author = "Sareetha Kailayangiri and Bianca Altvater and Stefanie Lesch and Sebastian Balbach and Claudia G{\"o}ttlich and Johanna K{\"u}hnemundt and Jan-Henrik Mikesch and Sonja Schelhaas and Silke Jamitzky and Jutta Meltzer and Nicole Farwick and Lea Greune and Maike Fluegge and Kornelius Kerl and Lode, {Holger N} and Nikolai Siebert and Ingo M{\"u}ller and Heike Walles and Wolfgang Hartmann and Claudia Rossig",
note = "Copyright {\textcopyright} 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = may,
day = "8",
doi = "10.1016/j.ymthe.2019.02.014",
language = "English",
volume = "27",
pages = "933--946",
journal = "MOL THER",
issn = "1525-0016",
publisher = "NATURE PUBLISHING GROUP",
number = "5",

}

RIS

TY - JOUR

T1 - EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells

AU - Kailayangiri, Sareetha

AU - Altvater, Bianca

AU - Lesch, Stefanie

AU - Balbach, Sebastian

AU - Göttlich, Claudia

AU - Kühnemundt, Johanna

AU - Mikesch, Jan-Henrik

AU - Schelhaas, Sonja

AU - Jamitzky, Silke

AU - Meltzer, Jutta

AU - Farwick, Nicole

AU - Greune, Lea

AU - Fluegge, Maike

AU - Kerl, Kornelius

AU - Lode, Holger N

AU - Siebert, Nikolai

AU - Müller, Ingo

AU - Walles, Heike

AU - Hartmann, Wolfgang

AU - Rossig, Claudia

N1 - Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

PY - 2019/5/8

Y1 - 2019/5/8

N2 - Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.

AB - Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.

KW - Journal Article

U2 - 10.1016/j.ymthe.2019.02.014

DO - 10.1016/j.ymthe.2019.02.014

M3 - SCORING: Journal article

C2 - 30879952

VL - 27

SP - 933

EP - 946

JO - MOL THER

JF - MOL THER

SN - 1525-0016

IS - 5

ER -