DNA VACCINATION IN TUMOR PREVENTION

Federica Cavallo, and Guido Forni

Department of Clinical and Biological Sciences, University of Turin, I-10043 Orbassano, Italy.

The question whether a vaccine can inhibit the progression of carcinogenesis is rarely addressed. Progression of a preneoplastic lesion is a lengthy process that may be hampered by mechanisms that are not efficacious when confronted with the unnatural speed of transplantable tumors. BALB/c female mice transgenic for the rat Her-2/neuT display one of the most aggressive Her-2/neu carcinogenesis. The protein product of the rat oncogene (rp185^neu) is already overexpressed by 3-4 week-old mice. At 6 weeks, rp185^neu cells give rise to a widespread mammary atypical hyperplasia which progresses to form an invasive and metastasizing carcinoma that becomes palpable in all ten mammary glands between the 22^nd and the 27^th week of age. Electroporations of plasmids coding for the extracellular and transmembrane domains of rp185^neu performed when mice display multifocal in situ carcinomas (week 10-12) temporarily halts neoplastic progression, and 47% of mice remained tumor free at one year of age when the experiment was ended. Two additional DNA electroporation courses at week 20-22 and week 30-32 extended the tumor free survival and no tumor was palpable until week 45. Finally, all mice that were electroporated at weeks 10-12, 20-22, 30-32, 40-42 were tumor free at one year of age. Pathological findings, in vitro tests, and the results from the immunization of both IFN-g and immunoglobulin gene knock out BALB-neuT mice, and of adoptive transfer experiments, all suggest that tumor clearance rests on the combination of low affinity antibodies and IFN-g releasing T cells. An appropriate vaccine effectively inhibits the progression of advanced and multifocal preneoplastic lesions. The aggressiveness and ineluctability of carcinogenesis of BALB-neuT mice makes this complete and persistent inhibition a significant finding.