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Gangliosides

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Abstract

Gangliosides are acidic glycosphingolipids that are expressed on the cell surface where they may play a role in the metastatic process and have proven to be uniquely potent targets for antibody-mediated immune attack using cancer vaccines or monoclonal antibodies. Five gangliosides are important targets for cancer therapy: GM2, GD2, and GD3 expressed primarily on tumors of neuroectodermal origin such as neuroblastomas, sarcomas, and melanomas; fucosyl GM1 expressed on small-cell lung cancers; and sialyl Lewisa (Lea), also known as CA19.9, expressed on cancers of the colon, pancreas, and breast. Vaccines and especially monoclonal antibodies targeting GD2, GD3, and sLea are able to prevent tumor establishment or slow tumor growth in preclinical models, but regression of visible or palpable tumors has proven more difficult. Recently, this has proven possible with radioimmune or antibody drug conjugates targeting sLea. These types of monoclonal antibody conjugates may represent the future of ganglioside-targeted therapy. Randomized clinical trials with vaccines targeting GM2, GD2, and GD3 gangliosides have been negative to date. However, randomized clinical trials with monoclonal antibodies targeting GD2 (UnituxinTM) in neuroblastoma patients have been positive, and UnituxinTM is now FDA approved for treatment of high-risk neuroblastoma patients. Radioimmune or antibody drug conjugates targeting gangliosides have not yet been tested in the clinic.

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References

  • Albertini MR, Hank JA, et al. Phase II trial of hu14.18-IL2 (EMD 273063) for patients with metastatic melanoma. J Clin Oncol. 2008;26:2008 (May 20 suppl; abstr 9039).

    Google Scholar 

  • Bennaceur K, Popa I, et al. Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis. Int Immunol. 2006;18(6):879–86.

    Article  CAS  PubMed  Google Scholar 

  • Cheresh DA, Pierschbacher MD, et al. Disialogangliosides GD2 and GD3 are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins. J Cell Biol. 1986;102(3):688–96.

    Article  CAS  PubMed  Google Scholar 

  • Cheung NK, Lazarus H, et al. Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol. 1987;5(9):1430–40.

    CAS  PubMed  Google Scholar 

  • Cheung NK, Kushner BH, et al. 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: a phase II study. Int J Oncol. 1998;12(6):1299–306.

    CAS  PubMed  Google Scholar 

  • Cheung IY, Sahota A, et al. Measuring circulating neuroblastoma cells by quantitative reverse transcriptase-polymerase chain reaction analysis. Cancer. 2004;101(10):2303–8.

    Article  PubMed  Google Scholar 

  • Eggermont A, Suciu S, et al. Randomized phase III trial comparing post-operative adjuvant ganglioside GM2-KLH-QS 21 vaccination treatment vs observation in stage II (T3-T4N0M0) melanoma: final results of the EORTC 18961 study. J Clin Oncol. 2010;28:7s. suppl; abstr 8505.

    Article  Google Scholar 

  • Hamilton WB, Helling F, et al. Ganglioside expression on human malignant melanoma assessed by quantitative immune thin-layer chromatography. Int J Cancer. 1993;53(4):566–73.

    Article  CAS  PubMed  Google Scholar 

  • Handgretinger R, Baader P, et al. A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother. 1992;35(3):199–204.

    Article  CAS  PubMed  Google Scholar 

  • Helling F, Shang A, et al. GD3 vaccines for melanoma: superior immunogenicity of keyhole limpet hemocyanin conjugate vaccines. Cancer Res. 1994;54(1):197–203.

    CAS  PubMed  Google Scholar 

  • Houghton JL, Zeglis BM, Abdel-Atti D, Aggeler R, Sawada R, Agnew BJ, Scholz WW, Lewis JS. Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer. Proc Natl Acad Sci. 2015;112:15850–5. UID26668398.

    Google Scholar 

  • Kirkwood JM, Manola J, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10(5):1670–7.

    Article  CAS  PubMed  Google Scholar 

  • Kushner BH, Cheung IY, Modak S, Kramer K, Ragupathi G, Cheung NKV. Phase I trial of a bivalent gangliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res. 2014;20:1375–82.

    Article  CAS  PubMed  Google Scholar 

  • Livingston PO, Ragupathi G. Carbohydrate vaccines against cancer. In: Kaufman HL, Wolchok JD, editors. General principles of tumor immunotherapy: basic and clinical applications of tumor immunology, Chapter 13. 1st ed. Netherland: Springer; 2007.

    Google Scholar 

  • Livingston PO, Wong GY, et al. Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol. 1994;12(5):1036–44.

    CAS  PubMed  Google Scholar 

  • Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murray JL, Cunningham JE, et al. Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors. J Clin Oncol. 1994;12(1):184–93.

    CAS  PubMed  Google Scholar 

  • Murray JL, Kleinerman ES, et al. Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma. J Immunother Emphasis Tumor Immunol. 1996;19(3):206–17.

    Article  CAS  PubMed  Google Scholar 

  • Nasi ML, Meyers M, et al. Anti-melanoma effects of R24, a monoclonal antibody against GD3 ganglioside. Melanoma Res. 1997;7 Suppl 2:S155–62.

    CAS  PubMed  Google Scholar 

  • Navid F, Santana VM, et al. Anti-GD2 antibody therapy for GD2-expressing tumors. Curr Cancer Drug Targets. 2010;10(2):200–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navid F, Sondel PM, Barfield R, Shulkin BL, Kaufman RA, Allay JA, Gan J, Hutson P, Seo S, Kim KM, Goldberg J, Hank JA, Billups CA, Wu J, Furman WL, McGregor LM, Otto M, Gillies SD, Handgretinger R, Santana VM. Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J Clin Oncol. 2014;32:1445–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Reilly EM, Bauer TM, Infante J, Gutheil JC, Klein P, Yu KH, Lowery MA, Livingston P, Martin P, Scholz W, Maffuid PW. Phase I trial of HuMab-5B1 (MVT-5873), a novel monoclonal antibody targeting sLea, in patients with advanced pancreatic cancer and other CA19-9 positive malignancies. In: Proceedings of the American Association of Cancer Researchers, vol. 57. 2016 (in press).

    Google Scholar 

  • Pule MA, Savoldo B, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14(11):1264–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ragupathi G, Liu NX, et al. Antibodies against tumor cell glycolipids and proteins, but not mucins, mediate complement-dependent cytotoxicity. J Immunol. 2005;174(9):5706–12.

    Article  CAS  PubMed  Google Scholar 

  • Reiter Y, Ciobotariu A, et al. Sublytic complement attack protects tumor cells from lytic doses of antibody and complement. Eur J Immunol. 1992;22(5):1207–13.

    Article  CAS  PubMed  Google Scholar 

  • Ritter G, Boosfeld E, et al. Antibody response to immunization with ganglioside GD3 and GD3 congeners (lactones, amide and gangliosidol) in patients with malignant melanoma. Int J Cancer. 1991;48(3):379–85.

    Article  CAS  PubMed  Google Scholar 

  • Saleh MN, Khazaeli MB, et al. Phase I trial of the murine monoclonal anti-GD2 antibody 14G2a in metastatic melanoma. Cancer Res. 1992;52(16):4342–7.

    CAS  PubMed  Google Scholar 

  • Sawada R, Sun SM, et al. Human monoclonal antibodies to sialyl-lewisa (CA19.9) with potent CDC, ADCC, and antitumor activity. Clin Cancer Res. 2011;17(5):1024–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shusterman S, London WB, et al. Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children’s Oncology Group (COG) phase II study. J Clin Oncol. 2008;26:2008 (May 20 suppl; abstr 3002).

    Google Scholar 

  • Viola-Villegas NT, Rice SL, Carlin S, Wu X, Evans MJ, Sevak KK, Drobjnak M, Ragupathi G, Sawada R, Scholz WW, Livingston PO, Lewis JS. Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology. J Nucl Med. 2013;54(11):113 UID24029655.

    Google Scholar 

  • Wu DY, Segal NH, et al. Cross-presentation of disialoganglioside GD3 to natural killer T cells. J Exp Med. 2003;198(1):173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Ragupathi G, Panageas K, Hong F, Livingston PO. Accelerated tumor growth mediated by sublytic levels of antibody-induced complement activation is associated with activation of the PI3K/AKT survival pathway. Clin Cancer Res. 2013;19:4728–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu AL, Uttenreuther-Fischer MM, et al. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol. 1998;16(6):2169–80.

    CAS  PubMed  Google Scholar 

  • Yu AL, Gilman AL, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang S, Cordon-Cardo C, et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosides. Int J Cancer. 1997;73(1):42–9.

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhang S, et al. Antibodies against GD2 ganglioside can eradicate syngeneic cancer micrometastases. Cancer Res. 1998;58(13):2844–9.

    CAS  PubMed  Google Scholar 

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Correspondence to Phil Livingston .

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© 2013 Springer Science+Business Media New York

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Livingston, P., Ragupathi, G. (2013). Gangliosides. In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6613-0_5-2

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  • DOI: https://doi.org/10.1007/978-1-4614-6613-0_5-2

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  • Online ISBN: 978-1-4614-6613-0

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