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Ganglioside conjugate vaccines

Immunotherapy against tumors of neuroectodermal origin

  • Published:
Molecular and chemical neuropathology

Abstract

Gangliosides are known to be suitable targets for immune attack against cancer but they are poorly immunogenic. Active immunization with ganglioside/BCG or liposome vaccines results in moderate titer IgM antibody responses of short duration. Covalent attachment of poorly immunogenic antigens to immunogenic proteins is a potent method for inducing an IgG antibody response. GD3, a dominant ganglioside on malignant melanoma, was modified by ozone cleavage of the double bond in the ceramide backbone, an aldehyde group introduced and used for coupling via reductive amination to ε-aminolysyl groups of proteins. Utilizing this method, GD3 conjugates were constructed with:

  1. 1.

    Synthetic multiple antigenic peptide (MAP) constructs expressing 4 repeats of a malaria T-cell epitope;

  2. 2.

    Outer membrane proteins (OMP) ofNeisseria meningitidis;

  3. 3.

    Cationized bovine serum albumin;

  4. 4.

    Keyhole limpet hemocyanin (KLH); and

  5. 5.

    Polylysine.

In addition, conjugates containing only the GD3 oligosaccharide were synthesized. All constructs were tested for antigenicity using anti-GD3 antibody R24, and for immunogenicity in mice. Serum antibody levels were analyzed by ELISA and immune thin-layer chromatography. Results in the mouse show a significant improvement in the IgM antibody response and a consistent IgG response against GD3 using GD3-KLH conjugates. Other carrier proteins and the use of GD3 oligosaccharide were significantly less effective. If improved immunogenicity and clinical benefit with conjugate vaccines can be demonstrated in patients with melanoma, this approach may be applicable to patients with other tumors of neuroectodermal origin, including gliomas, glioblastomas, astrocytomas, and neuroblastomas.

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References

  • Apple R.J., Domen P. L., Muckerheide A., and Michael J. G. (1988) Cationization of protein antigens: IV Increased antigen uptake by antigen presenting cells.J. Immunol. 40, 3290–3295.

    Google Scholar 

  • Carubia J. M., Yu R. K., Macala L. J., Kirkwood J. M., and Varga J. M. (1984) Gangliosides GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma.J. Clin. Oncol. 5, 1430–1440.

    Google Scholar 

  • Donnelly J. J., Deck R. R., and Liu M. A. (1991) Adjuvant activity of the outer membrane protein complex ofNeisseria meningitidis serogroup B for a polysaccharide-protein conjugate.Vaccines 91, 403–408.

    Google Scholar 

  • Hakomori S. I. (1985) Abberant glycosylation in cancer cell membranes as focused on glycolipides: Overview and perspectives.Cancer Res.45, 2405–2414.

    CAS  PubMed  Google Scholar 

  • Hamilton W. B., Helling F., Lloyd K. O., and Livingston P. O. (1993) Ganglioside expression on human malignant melanoma assessed by quantitative immune thin layer chromatography.Int. J. Cancer 53, 1–8.

    Article  Google Scholar 

  • Houghton A. N., Mintzer D., Cordon-Cardo C., Welt S., Fliegel B., Vadhan S., Carswell E., Melamed M. R., Oettgen H. F., and Old L. J. (1985) Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: A phase I trial in patients with malignant melanoma.Proc. Natl. Acad. Sci. USA 82, 1242–1246.

    Article  CAS  Google Scholar 

  • Kanfer J. N. and Hakomori S. (1983) Sphingolipid biochemistry, inHandbook of Lipid Research, vol. 3 (Hanahan D. J., ed.), pp. 49,50. Plenum, NY.

    Google Scholar 

  • Kensil C. R., Patel U., Lennick M., and Marciani D. (1991) Separation and characterization of Saponins with Adjuvant Activity fromQuillaja saponaria Molina Cortex.J. Immunol. 146, 431–437.

    CAS  PubMed  Google Scholar 

  • Landsteiner K. and Chase M. W. (1942) Experiments on transfer of cutaneous sensitivity to simple compounds.Proc. Soc. Exp. Biol. Med. 49, 688.

    Article  CAS  Google Scholar 

  • Livingston P. O. (1991) Active specific immunotherapy in the treatment of cancer, inImmunology and Allergy Clinics of North America: Human Cancer Immunology II, vol. II: 2, pp. 402–423. (Oettgen H. F., ed.), Saunders, London.

    Google Scholar 

  • Livingston P. O., Albino A. P., Chung T. J. C., Real F. X., Houghton A. N., Oettgen H. F., and Old L. J. (1985) Serological responses of melanoma patients to vaccines prepared from VSV lysates of autologous and allogeneic cultured melanoma cells.Cancer 55, 713–720.

    Article  CAS  Google Scholar 

  • Livingston P. O., Calves M. J., Helling F., Zollinger W. D., Blake M. S., and Lowell G. H. (1993) GD3/Proteosome vaccines induce consistent IgM antibodies against the ganglioside GD3.Vaccine 11, 1199–1204.

    Article  CAS  Google Scholar 

  • Livingston P. O., Natoli E. J., Jr., Calves M. J., Stockert E., Oettgen H. F., and Old L. J. (1987) Vaccines containing purified GM2 ganglioside elicit GM2 antibodies melanoma patients.Proc. Natl. Acad. Sci. USA 84, 2911–2915.

    Article  CAS  Google Scholar 

  • Livingston P. O., Oettgen H. F., and Old L. J. (1982) Specific active immunotherapy in cancer therapy, inImmunological Aspects of Cancer Therapeutics, (Mihich E., ed.), pp. 363–404. Wiley, NY.

    Google Scholar 

  • Livingston P. O., Ritter G., Srivastava P., Padavan M., Calves M. J., Oettgen H. F., et al. (1989) Characterization of IgG and IgM antibodies induced in melanoma patients by immunization with purified GM2 ganglioside.Cancer Res. 49, 7045–7050.

    CAS  PubMed  Google Scholar 

  • Livingston P. O., Takeyama H., Pollack M. S., Houghton A. N., Albino A., Pinsky C. M., Oettgen H. F., and Old L. J. (1983) Serological responses of melanoma patients to vaccines derived from allogeneic cultured melanoma cells.Int. J. Cancer 31, 567–575.

    Article  CAS  Google Scholar 

  • Livingston P. O., Watanabe T., Shiku H., Houghton A. N., Albino A., Takahashi T., Resnick L. A., Michitsch R., Pinsky C. M., Oettgen H. F., and Old L. J. (1982) Serological response of melanoma patients receiving melanoma cell vaccines. I. Autologous cultured melanoma cells.Int. J. Cancer 30, 413–422.

    Article  CAS  Google Scholar 

  • Livingston P. O., Wong G. Y., Adluri S., Tao Y., Padavan M., Parente R., Hanlon C., Calves M. J., Helling F., Ritter G., Oettgen H. F., and Old L. J. A randomized trial of adjuvant vaccination with BCG versus BCG plus the melanoma ganglioside GM2 in AJCC stage III melanoma patients.J. Clin. Oncol. in press.

  • Lowell G. H., Ballou W. R., Smith L. F., Wirtz R. A., Zollinger W. D., and Hockmeyer W. T. (1988b) Proteosome-lipopeptide vaccines: Enhancement of immunogenicity for malaria CS peptides.Science 240, 800–802.

    Article  CAS  Google Scholar 

  • Lowell G. H., Smith L. F., Seid R. C., and Zollinger W. D. (1988a) Peptides bound to proteosomes via hydrophobic feet become highly immunogenic without adjuvants.J. Exp. Med. 167, 658–663.

    Article  CAS  Google Scholar 

  • MacLean G. D., Bowen-Yacyshyn, M. B., Samuel J., Meikle A., Stuart G., Nation J., Poppema S., Jerry M., Koganty R., Wong T., and Longenecker B. M. (1992) Active immunization of human ovarian cancer patients against a common carcinoma (Thomsen-Friedenreich) determinant using a synthetic carbohydrate antigen.J. Immunother.11, 292–405.

    Article  CAS  Google Scholar 

  • Natoli E. J., Jr, Livingston P. O., Pukel C. S., Lloyd K. O., Wiegandt H., Szalay J., Oettgen H. F., and Old L. J. (1986) A murine monoclonal antibody detecting N-acetyl and N-glycolyl GM2: Characterization of cell surface reactivity.Cancer Res. 46, 4116–4120.

    CAS  PubMed  Google Scholar 

  • Neuenhofer S., Schwarzmann G., Egge H., and Sandhoff K. (1985) Synthesis of lysogangliosides.Biochemistry 24, 525–532.

    Article  CAS  Google Scholar 

  • Newman M. J., Wu J.-Y., Gardner B. H., Murroe K. J., Leombruno D., Recchia J., Kensil C. R., and Coughlin R. T. (1992) Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T-lymphocyte responses.J. Immunol. 148, 2357–2362.

    CAS  PubMed  Google Scholar 

  • Old L. J. (1981) Cancer immunology: The search for specificity-G. H. A. Clowes Memorial Lecture.Cancer Res. 41, 361–375.

    CAS  PubMed  Google Scholar 

  • Ravindranath M. H., Tsuchida, T., Morton D. L., and Irie R. F. (1991) Ganglioside GM3:GD3 ratio as an index for the management of melanoma.Cancer 67, 3029–3035.

    Article  CAS  Google Scholar 

  • Ritter G., Boosfeld E., Adluri R., Calves M., Oettgen H. F., Old L. J., and Livingston P. O. (1991) Antibody response to immunization with ganglioside GD3 and GD3 congeners (lactones, amide and gangliosidol) in patients with malignant melanoma.Int. J. Cancer 48, 379–385.

    Article  CAS  Google Scholar 

  • Tai T., Cahan L. D., Tsuchida T., Saxton R. E., Irie R. F., and Morton D. L. (1985) Immunogenicity of melanoma-associated gangliosides in cancer patients.Int. J. Cancer 53, 607–612.

    Article  Google Scholar 

  • Tam J. P. (1988) Synthetic peptide vaccine design: Synthesis and properties of a high-density multiple antigenic peptide system.Proc. Natl. Acad. Sci. USA 85, 5409–5413.

    Article  CAS  Google Scholar 

  • Tam J. P. and Lu Y. (1989) Vaccine engineering: Enhancement of immunogenicity of synthetic peptide vaccines related to hepatitis in chemically defined models consisting of T- and B-cell epitopes.Proc. Natl. Acad. Sci. USA 86, 9084–9088.

    Article  CAS  Google Scholar 

  • Thampoe I. J., Furukawa K., Vellve E., and Lloyd K. O. (1989) Sialytransferase levels and ganglioside expression in melanoma and other cultured human cancer cells.Cancer Res. 49, 6258–6264.

    CAS  PubMed  Google Scholar 

  • Tsuchida T., Saxton R. E., Morton D. L., and Irie R. F. (1987) Gangliosides of human melanoma.J. Natl. Cancer Inst. 78 I, 45–54.

    Article  Google Scholar 

  • Watanabe T., Pukel C. S., Takeyama H., Lloyd K. O., Shiku H., Li L. T. C., Travassos L. R., Oettgen H. F., and Old L. J. (1982) Human melanoma antigen AH is an autoantigenic ganglioside related to GD2.J. Exp. Med. 156, 1884–1888.

    Article  CAS  Google Scholar 

  • Wiegandt H. and Baschang G. (1965) Die Gewinnung des Zuckeranteils der Glykosphingolipide durch Ozonolyse und Fragmentierung.Z. Naturforschung 20b, 164–166.

    Article  CAS  Google Scholar 

  • Wilson R. E., Hager E. B., Hampers C. I., Corson J. M., Merill J. P., and Murray J. E. (1968) Immunologic rejection of human cancer transplanted with a renal allograft.N. Engl. J. Med. 278, 479–483.

    Article  CAS  Google Scholar 

  • Zukoski C. F., Killen D. A., Ginn, E., Matter B., Lucas D. O., and Siegler H. F. (1970) Transplanted carcinoma in immunosuppressed patients.Transplantation 9, 71–74.

    Article  Google Scholar 

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Authors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, 10021, New York, NY

    Friedhelm Helling & Philip O. Livingston

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  1. Friedhelm Helling
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  2. Philip O. Livingston
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Helling, F., Livingston, P.O. Ganglioside conjugate vaccines. Molecular and Chemical Neuropathology 21, 299–309 (1994). https://doi.org/10.1007/BF02815357

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  • DOI: https://doi.org/10.1007/BF02815357

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