Intensified antitumor immunity by a cancer vaccine that produces granulocyte-macrophage colony-stimulating factor plus interleukin 4.
Vaccination with irradiated tumor cells genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF tumor vaccine) induces a potent systemic antitumor immunity. To develop a protocol for cancer therapy to further augment the host immune response, we examined the effects of the GM-CSF tumor vaccines simultaneously producing additional cytokines. We prepared cancer vaccines expressing double cytokines by sequential recombinant retrovirus-mediated genetic transductions. We then used a murine intracerebral tumor model in which the GM-CSF tumor vaccine was less effective in immunopotentiation and evaluated tumor vaccines producing various cytokines in conjunction with GM-CSF. The cytokine combination of GM-CSF and interleukin 4 induced more potent antitumor immunity than GM-CSF alone. An in vivo depletion test showed that CD4+, CD8+, and asialoGM1+ cells were required for the optimum function of the GM-CSF plus interleukin 4 tumor vaccine. Histological examinations revealed infiltration of inflammatory cells at the site of tumor cell challenge as well as at the site of vaccination, indicating the induction of a systemic antitumor immune response which reached the central nervous system. Our findings suggest the feasibility of applying the intensified vaccination strategy to treat human cancers including malignant brain tumors.
Wakimoto
H
H
Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Cancer Institute, Tokyo, Japan.
Abe
J
J
Tsunoda
R
R
Aoyagi
M
M
Hirakawa
K
K
Hamada
H
H
D016475:3T3 Cells; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D007167:Immunotherapy; D015847:Interleukin-4 / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012190:Retroviridae; D014614:Vaccines, Synthetic
D016207:Cytokines; D014614:Vaccines, Synthetic; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor