Cancer vaccines: the interleukin 2 dosage effect.
Cancer vaccines genetically engineered to produce interleukin 2 have been investigated intensively in a series of animal models and are at the point of entering into clinical trials. In this study we demonstrate a strong correlation between the rate of interleukin 2 production and the protection efficiency of murine S91 melanoma cell (clone M-3) vaccines. Best immunization is achieved with vaccines producing medium interleukin 2 levels of 1000-3000 units per 10(5) cells per day. Reduced interleukin 2 production evokes a corresponding decline in the number of successfully treated animals. Unexpectedly, when interleukin 2 expression is raised to high levels of 5000-7500 units per 10(5) cells per day, protection is completely absent because of impaired generation of tumor-specific cytotoxic T lymphocytes. In comparison, granulocyte-macrophage colony-stimulating factor as immunomodulator induces substantial immunization even at a moderate level of secretion and protects all animals at the maximal obtainable level of secretion. Our findings demonstrate the importance of the interleukin 2 level produced by genetically modified tumor cells and may have substantial impact for the clinical application of cancer vaccines.
Schmidt
W
W
Research Institute of Molecular Pathology, Vienna, Austria.
Schweighoffer
T
T
Herbst
E
E
Maass
G
G
Berger
M
M
Schilcher
F
F
Schaffner
G
G
Birnstiel
M L
ML
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D007114:Immunization; D007115:Immunization Schedule; D007376:Interleukin-2 / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D010957:Plasmids; D015183:Restriction Mapping; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014612:Vaccines
D007376:Interleukin-2; D014612:Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor