Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.
To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.
Dranoff
G
G
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
Jaffee
E
E
Lazenby
A
A
Golumbek
P
P
Levitsky
H
H
Brose
K
K
Jackson
V
V
Hamada
H
H
Pardoll
D
D
Mulligan
R C
RC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000517:prevention & control; D015815:Cell Adhesion Molecules / Q000235:genetics; D003110:Colonic Neoplasms / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000517:prevention & control; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D007114:Immunization; D018799:Intercellular Adhesion Molecule-1; D007680:Kidney Neoplasms / Q000276:immunology* / Q000517:prevention & control; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000528:radiation effects
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D015815:Cell Adhesion Molecules; D018799:Intercellular Adhesion Molecule-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor