Nazha Bassel, Inal Cengiz, Owonikoko Taofeek K
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, United States.
Salem Veterans Affairs Medical Center, Salem, VA, United States.
Front Oncol. 2020 Jul 7;10:1000. doi: 10.3389/fonc.2020.01000. eCollection 2020.
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.
神经节苷脂是含碳水化合物的鞘脂，在正常组织中广泛表达，这使得大多数亚型不适合作为癌症治疗的靶点。然而，双唾液酸神经节苷脂GD2亚型在正常组织中表达有限，但在多种肿瘤中过度表达。双唾液酸神经节苷脂GD2可被视为一种肿瘤相关抗原，非常适合作为癌症治疗的靶点。双唾液酸神经节苷脂GD2通过增强细胞增殖、运动、迁移、黏附和侵袭参与肿瘤发生和恶性表型，具体取决于肿瘤类型。这为在癌症治疗中靶向双唾液酸神经节苷脂GD2提供了理论依据，推动了抗GD2单克隆抗体及其他治疗方法的研发。抗GD2单克隆抗体靶向表达GD2的肿瘤细胞，通过抗体依赖的细胞介导的细胞毒性作用导致吞噬和破坏，通过补体依赖的细胞毒性作用导致裂解，并通过直接诱导细胞死亡导致凋亡和坏死。抗GD2单克隆抗体还可能阻止循环中的恶性细胞归巢和黏附于细胞外基质。几乎所有神经母细胞瘤、大多数黑色素瘤和视网膜母细胞瘤、许多尤因肉瘤，以及在不同程度上，小细胞肺癌、神经胶质瘤、骨肉瘤和软组织肉瘤均高表达双唾液酸神经节苷脂GD2。用抗GD2单克隆抗体成功治疗表达双唾液酸神经节苷脂GD2的肿瘤受到多种药理学因素的阻碍，如抗体亲和力不足以介导抗体依赖的细胞介导的细胞毒性、抗体进入肿瘤微环境的穿透性不足，以及正常组织（如外周感觉神经纤维）中双唾液酸神经节苷脂GD2表达相关的毒性。尽管如此，抗GD2单克隆抗体地努图希单抗（ch14.18）已获美国食品药品监督管理局批准，地努图希单抗β（ch14.18/CHO）已获欧洲药品管理局批准用于治疗儿科患者的高危神经母细胞瘤。抗GD2疗法的临床试验目前正在其他类型表达双唾液酸神经节苷脂GD2的肿瘤患者以及神经母细胞瘤患者中进行。除抗GD2单克隆抗体外，抗GD2治疗方法还包括嵌合抗原受体T细胞疗法、双唾液酸神经节苷脂GD2疫苗、免疫细胞因子、免疫毒素、抗体药物偶联物、放射性标记抗体、靶向纳米颗粒和T细胞结合双特异性抗体。临床试验应进一步阐明抗GD2疗法对表达双唾液酸神经节苷脂GD2的恶性肿瘤的治疗潜力。
