Experientia

, Volume 50, Issue 7, pp 648–653 | Cite as

Efficacy of tumor cell vaccine after incorporating monophosphoryl lipid A (MPL) in tumor cell membranes containing tumor-associated ganglioside

  • M. H. Ravindranath
  • S. M. Brazeau
  • D. L. Morton
Research Articles

Abstract

Murine B16 melanoma expresses the ganglioside. GM3. GM3 shed from tumor cells is immunosuppressive and promotes tumor growth1. Reduction or elimination of the shed GM3 could be therapeutic, and the anti-GM3 antibodies may reduce and clear the shed ganglioside. To test this hypothesis, mice were challenged with tumor cells, with or without inducing anti-GM3 antibody response. Since gangliosides are poor immunogens and T-cell independent antigens, an adjuvant (monophosphoryl lipid A (MPL), a non-toxic lipid A ofSalmonella), directed against B-cells, was employed. MPL was incorporated onto liposomes and into the surface membrane of B16 mouse melanoma cells; both are rich in GM3. C57BL/6J mice immunized with MPL-liposomes or MPL-B16 cells responded with elevated levels of anti-GM3 IgM. Non-immunized mice or mice immunized with B16 cells alone or ganglioside GM3 alone (without MPL) elicited poor anti-GM3 IgM response, confirming the GM3's immunologic crypticity and MPL's immunopotentiating effect. MPL's immunopotentiating effect was improved by coupling it to melanoma cell membranes C57BL/6J mice were immunized with irradiated B16 alone or MPL alone or MPL-conjugated irradiated B16. After three weekly immunizations, each mouse received a challenge dose of viable syngeneic B16. Neither MPL alone nor B16 alone had a significant effect on tumor growth or host survival; however, administration of MPL-conjugated B16 cells significantly prevented tumor growth and prolonged survival. Our results indicate that MPL-incorporated B16 cells augment the anti-GM3 IgM response, which may reverse GM3-induced immunosuppression by eliminating tumor-derived GM3, and restore immunocompetence.

Key words

Tumor cell vaccine B16 melanoma gangliosides GM3 monophosphoryl lipid A (MPL) ELISA anti-GM3 IgM immunization 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Takahashi, K., Ono, K., Hirabayashi Y., and Taniguchi, M., J. Immun.140 (1988) 3244.Google Scholar
  2. 2.
    Ravindranath, M. H. and Morton, D. L., Int. Rev. Immun.7 (1991) 303.Google Scholar
  3. 3.
    Ravindranath, M. H. and Irie, R. F., in: Malignant Melanoma: Biology, Diagnosis and Therapy, p. 17. Ed. L. Nathanson, Kluwer Acad., Boston 1988.Google Scholar
  4. 4.
    Ravindranath, M. H., Paulson, J. C., and Irie, R. F., J. biol. Chem.263 (1988) 2079.Google Scholar
  5. 5.
    Wilschut, J., in: Methodologie des liposomes appliquee a la pharmacologie et a la biologies cellulaire, p. 10. Eds L. D. Leserman and J. Barbet, INSERM, Paris 1982.Google Scholar
  6. 6.
    Carr, C., Jr., and Morrison, D. C., Rev. infect. Dis.6 (1984) 497.Google Scholar
  7. 7.
    Shafer, W., and Spitznagel, J., Rev. infect. Dis.6 (1984) 577.Google Scholar
  8. 8.
    Freudenberg, M. A., Fomsgaard, A., Mitov, I., and Galnos, C., Infection17 (1989) 322.Google Scholar
  9. 9.
    Bekesi, J. G., Arneault, G. St., Walter, L., and Holland, J. F., J. natl Cancer Inst.49 (1972) 107.Google Scholar
  10. 10.
    Slingluff, C. L., Vollmer, R., and Seigler, H. F., J. surg. Oncol.39 (1988) 139.Google Scholar
  11. 11.
    Kobayashi, H., J. biol. Resp. Modif.5 (1986) 1.Google Scholar
  12. 12.
    Hirabayashi, Y., Hamaoka, A., Matsumoto, M., Matsubara, T., Tagawa, M., Wakabayashi, S., and Taniguchi, M., J. biol. Chem.260 (1985) 13328.Google Scholar
  13. 13.
    Hardings, C. V., Roof, R. W., Allen, P. M., and Unanue, E. R., Proc. natl Acad. Sci. USA,88 (1991) 2740–2746.Google Scholar
  14. 14.
    Ishioka, G. Y., Lamout, A. G., Thomson, D., Bullow, N., Gaeta, F. C. A., Sette, A., and Grey, H. M., J. Immun.148 (1992) 2446.Google Scholar
  15. 15.
    Dresser, D. W., and Philips, J. M., in: Immunopotentiation, p. 3. CIBA Foundation Symposium 18, Elsevier, Amsterdam 1973.Google Scholar
  16. 16.
    Schuster, B. G., Neidig, M., Alving, B. M., and Alving, C. R., J. Immun.122 (1979) 900.Google Scholar
  17. 17.
    Banerji, B., Lyon, J. A., and Alving, C. R., Biochim. biophys. Acta.689 (1982) 319.Google Scholar
  18. 18.
    Tamauchi, H., Tadakuma, T., Yasuda, T., Tsumita, T., and Saito, K., Immunology50 (1983) 605.Google Scholar
  19. 19.
    Vosika, G. J., Barr, C., and Gilbertson, D., Cancer Immun. Immunother.18 (1984) 107.Google Scholar
  20. 20.
    Harel, W., Shau, H., Hadley, C. G., Morgan, A. C., Reisfeld, R. A., Cheresh, D. A., and Mitchell, M. S., Cancer Res.50 (1990) 6311.Google Scholar
  21. 21.
    Livingston, P. O., Calves, M. J., and Natoli, E. J. Jr., J. Immun.138 (1987) 1524.Google Scholar
  22. 22.
    Irie, R. F., and Ravindranath, M. H., in: Theapeutic Monoclonal Antibodies, p. 75. Eds C. A. K. Borrebaeck and J. W. Larrick. Stockton Press, New York 1990.Google Scholar
  23. 23.
    Morton, D. L., and Ravindranath, M. H., in: Cancer Medicine, p. 967. 3rd Ed. Eds J. F. Holland, E. Frei III, R. C. Bast, D. W. Kufe, D. L. Morton and R. R. Weichselbaum. Lea & Febiger, Philadelphia 1993.Google Scholar
  24. 24.
    Bartlett, G. L., and Zbar, B., J. natl Cancer Inst.48 (1972) 1709.Google Scholar
  25. 25.
    Tanaka, T., and Takunaga, T., Gann62 (1971) 433.Google Scholar
  26. 26.
    Bast, R. C. Jr., Zbar, B., Borsos, T., and Rapp, H. J., N. Engl. J. Med.290 (1974) 1413.Google Scholar
  27. 27.
    Rosenberg, S. A., Lotze, M. T., and Yang J. C., Ann. Surg.210 (1989) 474.Google Scholar
  28. 28.
    Rosenberg, S. A., Packard, B. S., and Aebersold, P. M., N. Engl. J. Med.319 (1988) 1676.Google Scholar
  29. 29.
    Vadhan-Raj, S., Cordon-Cardo, C., Carswell, E., Mintzer, D., Dantis, L., Duteau, C., Templeton, M. A., Oettgen, H. F., Old, L. J., and Houghton, A. N., J. clin. Oncol.6 (1988) 1636.Google Scholar
  30. 30.
    Morton, D. L., Foshag, L. J., Hoon, D. S. B., Nizze, J. A., Wanek, L. A., Chang, C., Davtyan, D. G., Gupta, R. K., Elashoff, R., and Irie, R. F., Ann. Surg.216 (1992) 463.Google Scholar

Copyright information

© Birkhäuser Verlag 1994

Authors and Affiliations

  • M. H. Ravindranath
    • 1
  • S. M. Brazeau
    • 1
  • D. L. Morton
    • 1
  1. 1.Laboratory of Glycolipid ImmunotherapyJohn Wayne Cancer InstituteSanta MonicaUSA

Personalised recommendations