Vaccination with irradiated tumor cells genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF tumor vac cine) Induces a potent systemic antitumor immUnity. To develop a proto

Vaccination with irradiated tumor cells genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF tumor vac cine) Induces a potent systemic antitumor immUnity. To develop a proto eel for cancer therapy to further augment the host immune response, we examined the effects of the GM-CSF tumor vaccines simultaneously pro ducing additional cytokines. We prepared cancer vaccines expressing double cytokines by sequential recombinant retrovirus-mediated genetic transductlons. We then used a murine intracerebral tumor model in which the GM-CSF tumor vaccine was less effective In hnmunopotentiation and evaluated tumor vaccines producing various cytokines In conjunction with GM-CSF. The cytokine combination of GM-CSF and interleukin 4 In duced more potent antitumor immUnIty than GM-CSF alone. An in vivo depletion test showed that CD4@, CD8@, and asialoGMl' cells were required for the optimum function of the GM-CSF plus lnterleuldn 4 tumor vaccine. HIstOlOgIcalexaminations revealed infiltration of inflam matory 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 feasibilityof applyingthe Intensifiedvaccinationstrategyto treat human cancers Including malignant brain tumors.