Abstract
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.
Highlights
Cancer immunotherapy comprises different strategies that use distinct effector mechanisms of the immune system to target and eliminate tumor cells
The vast majority of these strategies have focused on protein antigens and recently monoclonal antibodies (mAbs) recognizing cell surface gangliosides have recently proven to be effective for cancer therapeutic targets [1]
The first GD2-Chimeric antigen receptor (CAR) was developed by Rossig et al based on single chain fragment variable (scFv) derived from the GD2-specific mAb 14G2a [118, 119] and was tested in Phase 1 clinical study [120, 121]
Summary
Cancer immunotherapy comprises different strategies that use distinct effector mechanisms of the immune system to target and eliminate tumor cells. Gangliosides are present on the outer leaflet of the plasma membrane with their hydrophobic ceramide backbone anchored in the membrane and their hydrophilic carbohydrate residue projected into the extracellular environment They are believed to be concentrated in ordered microdomains referred to as lipid rafts [11] where they can interact with different functional membrane proteins involved in cell adhesion and cell signaling [12]. It is important to note that patients treated with antiGD2 mAbs, such as dinutuximab, display dose-limiting acute toxicities, including hypotension, neuropathic pain, and fever upon antibody infusion [1] These side effects are related to dinutuximab binding on GD2-positive sensitive nerve fibers followed by complement activation [32, 35]. We will present the O-acetyl-GD2 tumor antigen and its potential interest for antibody-based immunotherapy and chimeric antigen receptor cellular immunotherapy
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