Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy

Abstract

Gangliosides are carbohydrate-containing sphingolipids that are widely expressed in normal tissues, making most subtypes unsuitable as targets for cancer therapy. However, the disialoganglioside GD2 subtype has limited expression in normal tissues but is overexpressed across a wide range of tumors. Disialoganglioside GD2 can be considered a tumor-associated antigen and well-suited as a target for cancer therapy. Disialoganglioside GD2 is implicated in tumor development and malignant phenotypes through enhanced cell proliferation, motility, migration, adhesion, and invasion, depending on the tumor type. This provides a rationale for targeting disialoganglioside GD2 in cancer therapy with the development of anti-GD2 monoclonal antibodies and other therapeutic approaches. Anti-GD2 monoclonal antibodies target GD2-expressing tumor cells, leading to phagocytosis and destruction by means of antibody-dependent cell-mediated cytotoxicity, lysis by complement-dependent cytotoxicity, and apoptosis and necrosis through direct induction of cell death. Anti-GD2 monoclonal antibodies may also prevent homing and adhesion of circulating malignant cells to the extracellular matrix. Disialoganglioside GD2 is highly expressed by almost all neuroblastomas, by most melanomas and retinoblastomas, and by many Ewing sarcomas and, to a more variable degree, by small cell lung cancer, gliomas, osteosarcomas, and soft tissue sarcomas. Successful treatment of disialoganglioside GD2-expressing tumors with anti-GD2 monoclonal antibodies is hindered by pharmacologic factors such as insufficient antibody affinity to mediate antibody-dependent cell-mediated cytotoxicity, inadequate penetration of antibody into the tumor microenvironment, and toxicity related to disialoganglioside GD2 expression by normal tissues such as peripheral sensory nerve fibers. Nonetheless, anti-GD2 monoclonal antibody dinutuximab (ch14.18) has been approved by the U.S. Food and Drug Administration and dinutuximab beta (ch14.18/CHO) has been approved by the European Medicines Agency for the treatment of high-risk neuroblastoma in pediatric patients. Clinical trials of anti-GD2 therapy are currently ongoing in patients with other types of disialoganglioside GD2-expressing tumors as well as neuroblastoma. In addition to anti-GD2 monoclonal antibodies, anti-GD2 therapeutic approaches include chimeric antigen receptor T-cell therapy, disialoganglioside GD2 vaccines, immunocytokines, immunotoxins, antibody-drug conjugates, radiolabeled antibodies, targeted nanoparticles, and T-cell engaging bispecific antibodies. Clinical trials should clarify further the potential of anti-GD2 therapy for disialoganglioside GD2-expressing malignant tumors.

Keywords: GD2; cancer therapy; clinical trials; dinutuximab; ganglioside; monoclonal antibody; neuroblastoma; small cell lung cancer.

Figure 1

Molecular structure of GD2. Gal, galactose; GalNAc, N-acetylgalactosamine; Glc, glucose; NeuNAc, N-acetylneuraminic acid. Adapted from: Ganglioside GD2. NIH. U.S. National Library of Medicine. National Center for Biotechnology Information. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/53481124.

Figure 2

Mechanisms of anti-GD2 mAbs and other therapeutic approaches [Source: Perez Horta et al. (66)]. The binding of anti-GD2 mAbs to GD2 on the surface of neuroblastoma cells results in three proposed antitumor effects: (1) attraction of NK cells, granulocytes, and other FCR-expressing effector cells to promote ADCC, together with the recruitment of macrophages and monocytes to mediate phagocytosis; (2) induction of CDC by binding of the mAb to complement component 1q (C1q), followed by activation of the complement cascade and transport of MAC to the plasma membrane of the tumor cell; and (3) direct cytotoxicity through the initiation of apoptosis. The concentration of IL-2-based immunocytokines at the tumor promotes activation of tumoricidal effector cells via their IL-2R and FC receptors. Radiolabeled mAbs serve the dual function of tumor radioimmunodetection and delivery of tumoricidal doses of radiation to tumor cells. Immunotoxins and drug conjugates can deliver various toxic agents to tumor cells, followed by internalization and release of the toxic agent and cell death. CAR-T cells are engineered ex vivo to recognize the tumor antigen and promote tumor cell lysis. Bispecific mAbs are available in a variety of forms such as hybrid bifunctional mAbs with two different antigen-specific regions or as BITE with the primary objective of redirecting T cells for tumor lysis by engaging tumor antigen and costimulatory molecules such as CD3. ADCC, antibody-dependent cell-mediated cytotoxicity; BITE, bispecific T-cell engagers; CAR, chimeric antigen receptor; CDC, complement-dependent cytotoxicity; FCR, FC-receptor; IL2, interleukin-2; IL2R, interleukin-2 receptor; mAb, monoclonal antibody; MAC, membrane attack complex. Reproduced with permission as agreed by Future Medicine Ltd.