Impairing Temozolomide Resistance Driven by Glioma Stem-like Cells with adjuvant Immunotherapy Targeting O-acetyl GD2 Ganglioside: A novel synergistic option for glioblastoma therapy

Julien Fleurence 1 Meriem Bahri 1 Sophie Fougeray 1, 2 Sébastien Faraj 3 Sarah Vermeulen 3 Émilie Pinault 4 Fanny Geraldo 5 Lisa Oliver 5 Joëlle Véziers 6, 7, 8 Pierre Marquet 9 Marion Rabé 5 Catherine Gratas 5 François Vallette 5, 10 Claire Pecqueur 1 François Paris 1, 10 Stéphane Birklé 1, 2, *
Abstract : Stem cell chemo-resistance is still challenging the efficacy of the front-line temozolomide against glioblastoma. Novel therapies are urgently needed to fight those cells in order to control tumor relapse. Here, we report that anti-O-acetyl-GD2 adjuvant immunotherapy controls glioma stem-like cell-driven chemo-resistance. Using patient-derived glioblastoma cells we found that glioma stem-like cells over-expressed O-acetyl-GD2. As a result, monoclonal antibody 8B6 immunotherapy significantly increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, the combination therapy decreased the expression of the glioma stem-like cell markers CD133 and Nestin and compromised glioma stem-like cell self-renewal capabilities. When tested in vivo, adjuvant 8B6 immunotherapy prevented the extension of the temozolomide-resistant glioma stem-like cell pool within the tumor bulk in vivo and was more effective than the single agent therapies. This is the first report demonstrating that anti-O-acetyl-GD2 monoclonal antibody 8B6 targets glioblastoma in a manner that control temozolomide-resistance driven by glioma stem-like cells. Together our results offer a proof of concept for using anti-O-acetyl GD2 reagents in glioblastoma to develop more efficient combination therapies for malignant gliomas. This article is protected by copyright. All rights reserved.
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Julien Fleurence, Meriem Bahri, Sophie Fougeray, Sébastien Faraj, Sarah Vermeulen, et al.. Impairing Temozolomide Resistance Driven by Glioma Stem-like Cells with adjuvant Immunotherapy Targeting O-acetyl GD2 Ganglioside: A novel synergistic option for glioblastoma therapy. International Journal of Cancer, Wiley, In press, Epub ahead of print. ⟨10.1002/ijc.32533⟩. ⟨inserm-02168202⟩

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