• Sareetha Kailayangiri, Bianca Altvater, Stefanie Lesch, Sebastian Balbach, Claudia Göttlich, Johanna Kühnemundt, Jan-Henrik Mikesch, Sonja Schelhaas, Silke Jamitzky, Jutta Meltzer, Nicole Farwick, Lea Greune, Maike Fluegge, Kornelius Kerl, Holger N Lode, Nikolai Siebert, Ingo Müller, Heike Walles, Wolfgang Hartmann, and Claudia Rossig.
• Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany.
• Mol. Ther. 2019 May 8; 27 (5): 933-946.

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

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