Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice

Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene d evelop early and multifocal mammary carcinomas. Within the first 5 months o f life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma . It was previously observed that chronic administration of interleukin (IL )-12 increased tumor latency, but every mouse eventually succumbed to multi ple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu comb ined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) ant igen must be expressed by allogeneic cells. IL-12 treatment strongly increa sed the cell vaccine efficacy. The mammary glands of mice receiving the com bined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci we re heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes . Specific anti-HER-2/neu antibodies were produced and a nonpolarized activ ation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was pro ven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2 /neu transgenic Balb/c juice. A possible requirement for IFN-gamma is relat ed to its effect oil antibody production, in particular oil IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that all allogeneic HER-2/neu-expressing cell va ccine combined with IL-12 systemic treatment call prevent the onset of gene tically determined tumors.