Adjuvant Ganglioside GM2-KLH/QS-21 Vaccination Versus Observation After Resection of Primary Tumor &gt; 1.5 mm in Patients With Stage II Melanoma: Results of the EORTC 18961 Randomized Phase III Trial

Eggermont, Alexander M.M.; Suciu, Stefan; Rutkowski, Piotr; Marsden, J.R.; Santinami, Mario; Corrie, Pippa; Aamdal, Steinar; Ascierto, Paolo A.; Patel, Poulam M.; Kruit, Wim; Bastholt, Lars; Borgognoni, Lorenzo; Bernengo, Maria Grazia; Davidson, N.; Polders, Larissa; Praet, Michel; Spatz, Alan

doi:10.1200/jco.2012.47.9303

Cited by 89 publications

(57 citation statements)

References 21 publications

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“…Current strategies using SBAs and cancer antigens (for example, NY-ESO-1) have proven to not only induce antibody responses, but also robust CD8+ T-cell expansion1737. Nevertheless, vaccinations with single injections of SBA-peptide compositions yielded only modest survival benefit for patients with established tumours56. Interestingly, when these vaccines were combined with TLR ligands like CpG-ODN5758, or followed up by a boosting regimen59, beneficial correlates of immunological protection could greatly be improved.…”

Section: Discussionmentioning

confidence: 99%

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

et al. 2016

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Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity.

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Section: Discussionmentioning

confidence: 99%

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

et al. 2016

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“…In the ongoing clinical trials, the NeuGc GM3/VSSP and Racotumomab vaccines show efficacy and are well-tolerated by patients with advanced cutaneous melanoma (148) and NSCLC (149), respectively. This represents a significant step forward from the first, unsuccessful, attempt of developing a ganglioside-based vaccine – the GMK (GM2-based) vaccine for melanoma (150, 151). These molecules are part of a growing arsenal of targeted molecular weapons against cancer, which may be used as stand-alone therapy, but will more likely be employed as adjuvant therapy, in combination with or following standard treatment such as surgery, radiation, or chemotherapy.…”

Section: Ganglioside-based Therapymentioning

confidence: 99%

Molecular Recognition of Gangliosides and Their Potential for Cancer Immunotherapies

Krengel

Bousquet

2014

Front. Immunol.

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Gangliosides are sialic-acid-containing glycosphingolipids expressed on all vertebrate cells. They are primarily positioned in the plasma membrane with the ceramide part anchored in the membrane and the glycan part exposed on the surface of the cell. These lipids have highly diverse structures, not the least with respect to their carbohydrate chains, with N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) being the two most common sialic-acid residues in mammalian cells. Generally, human healthy tissue is deficient in NeuGc, but this molecule is expressed in tumors and in human fetal tissues, and was hence classified as an onco-fetal antigen. Gangliosides perform important functions through carbohydrate-specific interactions with proteins, for example, as receptors in cell–cell recognition, which can be exploited by viruses and other pathogens, and also by regulating signaling proteins, such as the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), through lateral interaction in the membrane. Through both mechanisms, tumor-associated gangliosides may affect malignant progression, which makes them attractive targets for cancer immunotherapies. In this review, we describe how proteins recognize gangliosides, focusing on the molecular recognition of gangliosides associated with cancer immunotherapy, and discuss the importance of these molecules in cancer research.

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“…The GM2-KLH vaccine not only induced a IgM response, but also induced durable IgG antibodies in most patients in early clinical trials (76). Nevertheless, a recent study shows that GM2-KLH/QS-21 vaccination does not improve the outcome for patients with stage II melanoma (77). …”

Section: Immunotherapies Using Ganglioside Gm2 As the Targetmentioning

confidence: 99%

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

et al. 2013

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Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.

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Adjuvant Ganglioside GM2-KLH/QS-21 Vaccination Versus Observation After Resection of Primary Tumor > 1.5 mm in Patients With Stage II Melanoma: Results of the EORTC 18961 Randomized Phase III Trial

Abstract: GM2-KLH/QS-21 vaccination does not improve outcome for patients with stage II melanoma.

Cited by 89 publications

References 21 publications

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

Molecular Recognition of Gangliosides and Their Potential for Cancer Immunotherapies

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

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