Vaccines against human HER2 prevent mammary carcinoma in mice transgenic for human HER-2.

open17siThis work was supported by grants from the Italian Association for Cancer Research (AIRC), Milan, Italy (project 10353); the Department of Experimental Pathology, University of Bologna (Pallotti funds); the University of Bologna Ricerca Fondamentale Orientata (RFO); and the Italian Ministry for University and Research (PRIN 2008 and 2009 projects).INTRODUCTION: The availability of mice transgenic for the human HER2 gene (huHER2) and prone to the development of HER2-driven mammary carcinogenesis (referred to as FVB-huHER2 mice) prompted us to study active immunopreventive strategies targeting the human HER2 molecule in a tolerant host. METHODS: FVB-huHER2 were vaccinated with either IL-12-adjuvanted human HER2-positive cancer cells or DNA vaccine carrying chimeric human-rat HER2 sequences. Onset and number of mammary tumors were recorded to evaluate vaccine potency. Mice sera were collected and passively transferred to xenograft-bearing mice to assess their antitumor efficacy. RESULTS: Both cell and DNA vaccines significantly delayed tumor onset, leading to about 65% tumor-free mice at 70 weeks, whereas mock-vaccinated FVB-huHER2 controls developed mammary tumors at a median age of 45 weeks. In the DNA vaccinated group, 65% of mice were still tumor-free at about 90 weeks of age. The number of mammary tumors per mouse was also significantly reduced in vaccinated mice. Vaccines broke the immunological tolerance to the huHER2 transgene, inducing both humoral and cytokine responses. The DNA vaccine mainly induced a high and sustained level of anti-huHER2 antibodies, the cell vaccine also elicited interferon (IFN)-gamma production. Sera of DNA-vaccinated mice transferred to xenograft-carrying mice significantly inhibited the growth of human HER2-positive cancer cells. CONCLUSIONS: Anti-huHER2 antibodies elicited in the tolerant host exert antitumoral activity.openDE GIOVANNI, Carla; Nicoletti, Giordano; Quaglino, E; Landuzzi, Lorena; Palladini, Arianna; Ianzano, MARIANNA LUCIA; Dall'Ora, Massimiliano; Grosso, Valentina; Ranieri, Dario; Laranga, Roberta; Croci, Stefania; Amici, A; Penichet, Ml; Iezzi, M; Cavallo, F; Nanni, Patrizia; Lollini, PIER LUIGIDE GIOVANNI, Carla; Nicoletti, Giordano; Quaglino, E; Landuzzi, Lorena; Palladini, Arianna; Ianzano, MARIANNA LUCIA; Dall'Ora, Massimiliano; Grosso, Valentina; Ranieri, Dario; Laranga, Roberta; Croci, Stefania; Amici, A; Penichet, Ml; Iezzi, M; Cavallo, F; Nanni, Patrizia; Lollini, PIER LUIG