Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and 
sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung 
cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma in 
children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma 
and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues 
is restricted to the brain, which is inaccessible to circulating antibodies, and 
in selected peripheral nerves and melanocytes, it was deemed a suitable target 
for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested 
in clinical trials for neuroblastoma for over the past two decades, with proven 
safety and efficacy. The main limitations have been acute pain toxicity 
associated with GD2 expression on peripheral nerve fibers and the inability of 
antibodies to treat bulky tumor. Several strategies have been developed to 
reduce pain toxicity, including bypassing complement activation, using blocking 
antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on 
peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal 
antibodies and fragments have been engineered into immunocytokines, 
immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted 
nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen 
receptors. The challenges of these approaches will be reviewed to build a 
perspective for next generation anti-GD2 therapeutics in cancer therapy.