- IL‐2 gene was introduced through retroviral vectors into the highly malignant and poorly immunogenic 3LL‐D122 clone. Both high and low D122‐11‐2 secretors showed elimination of tumorigenicity in syngeneic immune‐competent mice; however, in nude mice only the high IL‐2 secretor showed reduced tumorigenicity as compared with parental D 122 cells. Also, following intravenous inoculation, only the high IL‐2 secretor showed reduced generation of metastases, whereas the low IL‐2 secretors were as highly metastatic as parental cells. These results seem to indicate that low levels of IL‐2 secreted by tumor cells are sufficient to activate T cells, while higher levels are needed in order to activate non‐T‐cell effectors. D122‐IL‐2 secretors induced high levels of anti‐tumor CTL, while their sensitivity to the lytic activity of these CTL was similar to the sensitivity of D122 cells, thus indicating that the elevation of immunogenicity of IL‐2 secretors was essentially due to the secreted IL‐2. In accordance with CTL induction, pre‐immunization with IL‐2 secretors protected mice against subsequent challenge of parental cells. Moreover, immunization in an “immunotherapy protocol” i.e., vaccination of mice carrying an established tumor of parental D122 cells with inactivated D122‐IL‐2 infectants, almost completely eliminated the generation of lung metastases by D122 cells, thus providing a rationale for the use of IL‐2 gene transferred tumor cells as a modality for treatment of metastasis.