Prospects of anti-GD2 immunotherapy for retinoblastoma

Abstract

Retinoblastoma is the most common type of eye tumor in infants and children. Current treatments for retinoblastoma include intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, cryotherapy, radiotherapy, and surgery. However, these treatments come accompanied by adverse effects such as the toxic side effects of chemotherapeutic drugs, post-operative complications including blindness after surgery, or other complications caused by radiotherapy. Immunotherapy is more promising for its low toxicity on normal cells and effectively improves the quality of life of patients. Disialoganglioside (GD2), a sphingolipid expressed on the surface of retinoblastoma, is a potential therapeutic target for retinoblastoma. We summarized immunotherapeutic approaches for both preclinical studies and clinical trials of GD2. An anti-GD2 monoclonal antibody (Dinutuximab), which has been approved for the treatment of high-risk neuroblastomas, has shown promising efficacy in improving patients' prognosis. Additionally, chimeric antigen receptors (CAR)-T therapy, GD2 vaccines and nanoparticles are also potential therapeutics. Finally, we discuss the prospects and current limitations of these immunotherapeutic approaches for treating retinoblastoma, as well as how to address these problems.

Keywords: GD2; GD2-CAR cell therapy; anti-GD2 monoclonal antibody; immunotherapy; retinoblastoma.

Figure 1

The biosynthetic process of GD2. Ceramide (Cer) is first synthesised in the endoplasmic reticulum (ER), ① Cer transfers to the inner Golgi (cytoplasmic side) via vesicles or ceramide transfer protein (CERT), ② Cer binds to glucose to produce glucosylceramide (GlcCer), ③ GlcCer is transferred to the cytoplasmic face of the ER via FAPP2 (phosphatidylinositol 4-phosphate adaptor protein), ④ GlcCer is flipped to the luminal side of the ER by ATP-independent flippase, ⑤ GlcCer in the lumen of the ER is translocated to the Golgi via vesicles, ⑥ GlcCer binds to galactose in the Golgi to form lactosylceramide (LacCer), ⑦ LacCer binds to salivary acid (Neu5Ac) to produce GM3, ⑧ GM3 continues to bind to Neu5Ac to generate GD3, ⑨ GD3 binds to N-acetylgalactosamine (GalNAc) to produce GD2, ⑩ GD2 is transferred to the cell membrane via vesicles secreted by the Golgi apparatus.

Figure 2

Immunotherapeutic mechanisms on GD2. (A) Binding of the Fc segment of the antibody to the FcR of the effector cell (e.g. granulocyte) initiates the killing of the cell. (B) Antibodies mediate tumour cell lysis via complement-dependent cytotoxicity. (C) Antibodies directly induce cell death. (D) CAR-T cells recognize GD2 and promote cell lysis. (E) Nanoparticles recognize GD2 by antibodies and deliver cytotoxic drugs and RNA to tumour cells.