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Original Article

¹ Cancer Research Section, Department of Experimental Pathology, University of Bologna
² IST Biotechnology Satellite Unit, I-40126 Bologna, Italy
³ Department of Oncology and Neurosciences, "G. D'Annunzio" University, I-66100 Chieti, Italy
⁴ Department of Clinical and Biological Sciences, University of Turin, I-10043 Orbassano, Italy
⁵ Experimental Medicine Research Center S. Giovanni Battista Hospital, I-10126 Turin, Italy
⁶ Molecular Targeting Unit, National Cancer Institute, I-20133 Milan, Italy
⁷ Immunotherapy and Gene Therapy Unit, National Cancer Institute, I-20133 Milan, Italy

Address correspondence to Pier-Luigi Lollini, Sezione di Cancerologia, Viale Filopanti 22, I-40126 Bologna, Italy. Phone: 390-51-241-110; Fax: 390-51-242-169; E-mail: pierluigi{at}lollini.dsnet.it

Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of 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 multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185^neu antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8⁺ lymphocytes. Specific anti–HER-2/neu antibodies were produced and a nonpolarized activation of CD4⁺ and CD8⁺ cells secreting IL-4 and interferon (IFN)- were evident. A central role for IFN- in the preventive effect was proven by the lack of efficacy of vaccination in IFN- gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN- is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN- knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu–expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

Key Words: IL-12 • allogeneic vaccine • HER-2/neu • mammary carcinoma • immunoprevention

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