Search

Stem cell chemoresistance remains 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 chemoresistance. Using patient‐derived glioblastoma cells, we found that glioma stem‐like cells overexpressed 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. What's new? Glioblastoma multiforme (GBM) is a complex malignancy harboring differentiated tumor‐bulk cells and self‐renewing GBM stem‐like cells (GSCs). Targeting both cell compartments is necessary to improve prognosis. Here, the authors characterize OAcGD2 ganglioside as a novel GSCs marker that sensitizes chemo‐resistant GSCs to TMZ. The combination of anti‐OAcGD2 monoclonal antibody 8B6 with TMZ results in increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, 8B6 works synergistically with TMZ to compromise GSCs self‐renewal. The identification of OAcGD2 as a GSC‐associated antigen offers a novel opportunity for optimizing TMZ chemotherapy in GBM patients to prevent recurrence. [ABSTRACT FROM AUTHOR]

Target selection is a key feature in cancer immunotherapy, a promising field in cancer research. In this respect, gangliosides, a broad family of structurally related glycolipids, were suggested as potential targets for cancer immunotherapy based on their higher abundance in tumors when compared with the matched normal tissues. GD2 is the first ganglioside proven to be an effective target antigen for cancer immunotherapy with the regulatory approval of dinutuximab, a chimeric anti-GD2 therapeutic antibody. Although the therapeutic efficacy of anti-GD2 monoclonal antibodies is well documented, neuropathic pain may limit its application. O-Acetyl-GD2, the O-acetylated-derivative of GD2, has recently received attention as novel antigen to target GD2-positive cancers. The present paper examines the role of O-acetyl-GD2 in tumor biology as well as the available preclinical data of anti-O-acetyl-GD2 monoclonal antibodies. A discussion on the relevance of O-acetyl-GD2 in chimeric antigen receptor T cell therapy development is also included. [ABSTRACT FROM AUTHOR]