Cancer immunotherapy has become one of the most flourishing fields in medicine. However, the number of targets for the approved cancer immunotherapy has remained small, and limited to proteins. The approval of Dinutuximab, an anti-GD2 antibody, in 2015 for treating high-risk neuroblastoma marks the first new agent targeting a glycolipid molecule, largely based on the pioneer work of Dr. Yu. The benefit of immunotherapy with anti-GD2 has been confirmed in the long term follow up of the pivotal phase III randomized trial and a large cohort (n=1183) of non-randomized study. Strategies to improve its efficacy include combination with chemotherapy, DFMO or anti-PD1, humanization of anti-GD2, and GD2-CAR cell therapy. In 2020, a humanized anti-GD2 Naxitamab received FDA approval for relapsed/refractory neuroblastoma. An antibody against 9- O-acetyl derivative of GD2 (OAcGD2) which was highly expressed in neuroectodermal tumors but not normal neurons, displayed significant anti-tumor efficacy without neuropathic pain associated with anti-GD2. We demonstrated OAcGD2 to be a novel marker for breast cancer stem cells (CSC) and anti-OAcGD2 may target CSC to reduce cancer metastasis and recurrence.
　　Another glycolipid, Globo H, is the most prevalent cancer-associated antigens, and an ideal target for cancer immunotherapy. Clinically, expression of Globo H has been reported in 7 types of epithelial cancers. High expression of Globo H is an independent poor prognostic factor for breast cancer, hepatoma, cholangiocarcinoma and gallbladder cancer. Globo H ceramide (GHCer) can shape the tumor microenvironment to facilitate tumor growth. After shedding from tumor cells to extracellular vesicles, GHCer is incorporated into endothelial cells to promote angiogenesis. GHCer is also taken up by immune cells, suppressing T cell activation but promote expansion/function of Treg. Such dual immunosuppressive activities of GHCer are mediated by activation of adenosine A2A receptor (A2AR) / cAMP/PKA signaling pathway. Thus, GHCer is not only a poor prognostic tumor marker but also acts as an immune checkpoint and an angiogenic factor to shape the tumor microenvironment. These findings provide strong rationales for developing Globo H-targeted immunotherapy. A randomized multinational phase II trial of Globo H-KLH vaccine in metastatic breast cancer showed improved progression free survival in patients who mounted anti-Globo H immune responses, thereby providing the basis for the ongoing global phase III trial. In addition, a 2nd generation Globo H vaccine, an anti-Globo H and its ADC have completed phase I trials with ongoing phase II expansion studies.