Efficacy of tumor cell vaccine after incorporating monophosphoryl lipid A (MPL) in tumor cell membranes containing tumor-associated ganglioside.
Murine B16 melanoma expresses the ganglioside GM3. GM3 shed from tumor cells is immunosuppressive and promotes tumor growth. 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 of Salmonella), 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.
Laboratory of Glycolipid Immunotherapy, John Wayne Cancer Institute, Santa Monica, California 90404.
M H
MH
Ravindranath
S M
SM
Brazeau
D L
DL
Morton
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005679:G(M3) Ganglioside / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007121:Immunocompetence; D007075:Immunoglobulin M / Q000096:biosynthesis; D016233:Immunotherapy, Active; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014612:Vaccines / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D005679:G(M3) Ganglioside; D007075:Immunoglobulin M; D008050:Lipid A; D008081:Liposomes; D014612:Vaccines; C048436:monophosphoryl lipid A