Article

DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies.

Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Cancer Research (Impact Factor: 9.28). 10/2008; 68(18):7502-11. DOI: 10.1158/0008-5472.CAN-08-1489
Source: PubMed

ABSTRACT Her-2/neu(+) tumor cells refractory to antibody or receptor tyrosine kinase inhibitors are emerging in treated patients. To investigate if drug resistant tumors can be controlled by active vaccination, gefitinib and antibody sensitivity of four neu(+) BALB/c mouse mammary tumor lines were compared. Significant differences in cell proliferation and Akt phosphorylation were observed. Treatment-induced drug resistance was associated with increased chromosomal aberrations as shown by spectral karyotyping analysis, suggesting changes beyond neu signaling pathways. When mice were immunized with pneuTM encoding the extracellular and transmembrane domains of neu, antibody and T-cell responses were induced, and both drug-sensitive and drug-resistant tumor cells were rejected. In T-cell-depleted mice, drug-sensitive tumors were still rejected by vaccination, but drug-refractory tumors survived in some mice, indicating their resistance to anti-neu antibodies. To further test if T cells alone can mediate tumor rejection, mice were immunized with pcytneu encoding full-length cytoplasmic neu that is rapidly degraded by the proteasome to activate CD8 T cells without inducing antibody response. All test tumors were rejected in pcytneu-immunized mice, regardless of their sensitivity to gefitinib or antibody. Therefore, cytotoxic T lymphocytes activated by the complete repertoire of neu epitopes were effective against all test tumors. These results warrant Her-2 vaccination whether tumor cells are sensitive or resistant to Her-2-targeted drugs or antibody therapy.

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    • "Given the importance of danger signals in initiating immunity, we propose that blocking oncogenic signals by the anti-HER2/neu antibody may be an important initiator of, and positive-feedback loop for, adaptive immunity. For instance, antibody treatment of a neu + transfected tumor line, that is not dependent on a HER2/neu signal for its growth, does not reverse tumor growth in vitro and fails to demonstrate any effect on in vivo tumor growth (Whittington et al., 2008). We also observed that tyrosine kinase inhibitor treatment is very potent in blocking oncogenic signals in vitro, but anti-neu antibody is more potent in vivo, presumably because of the additional FcR-mediated effect. "
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