DNA Vaccination Controls Her-2+ Tumors that Are Refractory to Targeted Therapies

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. [Cancer Res 2008;68(18):7502-11]

Mesenchymal Stromal Cells Expressing ErbB-2/neu Elicit Protective Antibreast Tumor Immunity In vivo, Which Is Paradoxically Suppressed by IFN-γ and Tumor Necrosis Factor-α Priming

“…The effectiveness of the MSC/Neu vaccines was tested in transplantation models employing TUBO cells, derived from NeuT transgenic mice, and D2F2/neu cells, generated by transfection of D2F2 mammary tumor cells with a neuexpressing vector (14). It was previously shown in vivo that TUBO cell growth was inhibited by anti-neu antibody and CTL responses, whereas D2F2/neu cell regression depended on the induction of strong CTL responses (16). Using a prophylactic protocol, we observed that immunization with allogeneic MSC/Neu protected against TUBO but not against D2F2/ neu cell challenges (Fig.…”

“…D2F2 cells were derived from a mouse mammary tumor that arose in a BALB/c hyperplastic alveolar nodule. D2F2/neu cells (16) were obtained from D2F2 cells after transfection with pCMV/ neu encoding the transforming rat neu, and were kindly provided by Dr. Wei-Zen Wei (Wayne State University, Detroit, MI). Cell lines were not authenticated.…”

“…Neu-specific antibody responses were measured in sera of individual mice by a flow cytometry-based assay, as described (16 (19) epitopes from the rat neu antigen, respectively. Peptides were synthesized at the McGill Sheldon Biotechnology Center with purity above 98%.…”

Vaccine-Elicited CD8+ T Cells Cure Mesothelioma by Overcoming Tumor-Induced Immunosuppressive Environment

“…So far, conventional DNA vaccines have little therapeutic efficacy against solid tumors (22,23). To determine the therapeutic effects of sPD1-p24 fc /EP, mice were first inoculated subcutaneously with the lethal dose of AB1-GAG cells followed by sPD1-p24 fc /EP, p24 fc /EP or sham vaccination the next day and every 2 weeks for four times (Fig.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…HER2/neu has been targeted using polynucleotide or DNA vaccine strategies involving both syngeneic and xenogeneic sequences, the latter to improve the magnitude of elicited immune responses [246][247][248][249][250][251][252][253][254], in prime boost strategies combining DNA vaccines with viral vector-based vaccines [255] and with gene-modified allogeneic cellular vaccines (NCT00095862) [256]. Viral vector vaccine strategies using adenovirus vectors [257][258][259][260], alphavirus vectors [212,213,261], vaccinia virus vectors (NCT00485277 and NCT01152398), vesicular stomatitis virus [262] and polyoma virus systems [263,264] have all been used to elicit anti-HER2/neu immune responses.…”