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Immunology |
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [R. T. R., M. B. C. G., A. M. E., J-P. H. M., C. E. K., F. I. O., E. M. J.]; Genetic Therapy, Inc., Gaithersburg, Maryland 20878 [K. H. D.]; and Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada L8S 4K1 [W. J. M.]
HER-2/neu (neu-N) transgenic mice, which express the nontransforming rat proto-oncogene, develop spontaneous focal mammary adenocarcinomas beginning at 5–6 months of age. The development and histology of these tumors bears a striking resemblance to what is seen in patients with breast cancer. We have characterized the immunological responses to HER-2/neu (neu) in this animal model. neu-positive tumor lines, which were derived from spontaneous tumors that formed in neu-N animals, are highly immunogenic in parental, FVB/N mice. In contrast, a 100-fold lower tumor challenge is sufficient for growth in 100% of transgenic animals. Despite significant tolerance to the transgene, neu-specific immune responses similar to those observed in breast cancer patients can be demonstrated in neu-N mice prior to vaccination. Both cellular and humoral neu-specific responses in transgenic mice can be boosted with neu-specific vaccination, although to a significantly lesser degree than what is observed in FVB/N mice, indicating that the T cells involved are less responsive than in the nontoleragenic parental strain. Using irradiated whole-cell and recombinant vaccinia virus vaccinations we are able to protect neu-N mice from a neu-expressing tumor challenge. T-cell depletion experiments demonstrated that the observed protection is T cell dependent. The vaccine-dependent neu-specific immune response is also sufficient to delay the onset of spontaneous tumor formation in these mice. These data suggest that, despite tolerance to neu in this transgenic model, it is possible to immunize neu-specific T cells to achieve neu-specific tumor rejection in vivo. These transgenic mice provide a spontaneous tumor model for identifying vaccine approaches potent enough to overcome mechanisms of immune tolerance that are likely to exist in patients with cancer.
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M. P. Piechocki, Y.-S. Ho, S. Pilon, and W.-Z. Wei Human ErbB-2 (Her-2) Transgenic Mice: A Model System for Testing Her-2 Based Vaccines J. Immunol., December 1, 2003; 171(11): 5787 - 5794. [Abstract] [Full Text] [PDF]
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M. E. Wolpoe, E. R. Lutz, A. M. Ercolini, S. Murata, S. E. Ivie, E. S. Garrett, L. A. Emens, E. M. Jaffee, and R. T. Reilly HER-2/neu-Specific Monoclonal Antibodies Collaborate with HER-2/neu-Targeted Granulocyte Macrophage Colony-Stimulating Factor Secreting Whole Cell Vaccination to Augment CD8+ T Cell Effector Function and Tumor-Free Survival in Her-2/neu-Transgenic Mice J. Immunol., August 15, 2003; 171(4): 2161 - 2169. [Abstract] [Full Text] [PDF]
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V. Renard, L. Sonderbye, K. Ebbehoj, P. B. Rasmussen, K. Gregorius, T. Gottschalk, S. Mouritsen, A. Gautam, and D. R. Leach HER-2 DNA and Protein Vaccines Containing Potent Th Cell Epitopes Induce Distinct Protective and Therapeutic Antitumor Responses in HER-2 Transgenic Mice J. Immunol., August 1, 2003; 171(3): 1588 - 1595. [Abstract] [Full Text] [PDF]
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D. Artemov, N. Mori, R. Ravi, and Z. M. Bhujwalla Magnetic Resonance Molecular Imaging of the HER-2/neu Receptor Cancer Res., June 1, 2003; 63(11): 2723 - 2727. [Abstract] [Full Text] [PDF]
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A. M. Ercolini, J.-P. H. Machiels, Y. C. Chen, J. E. Slansky, M. Giedlen, R. T. Reilly, and E. M. Jaffee Identification and Characterization of the Immunodominant Rat HER-2/neu MHC Class I Epitope Presented by Spontaneous Mammary Tumors from HER-2/neu-Transgenic Mice J. Immunol., April 15, 2003; 170(8): 4273 - 4280. [Abstract] [Full Text] [PDF]
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S. C. Hewitt, W. P. Bocchinfuso, J. Zhai, C. Harrell, L. Koonce, J. Clark, P. Myers, and K. S. Korach Lack of Ductal Development in the Absence of Functional Estrogen Receptor {alpha} Delays Mammary Tumor Formation Induced by Transgenic Expression of ErbB2/neu Cancer Res., May 1, 2002; 62(10): 2798 - 2805. [Abstract] [Full Text] [PDF]
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P. Nanni, G. Nicoletti, C. De Giovanni, L. Landuzzi, E. Di Carlo, F. Cavallo, S. M. Pupa, I. Rossi, M. P. Colombo, C. Ricci, et al. Combined Allogeneic Tumor Cell Vaccination and Systemic Interleukin 12 Prevents Mammary Carcinogenesis in HER-2/neu Transgenic Mice J. Exp. Med., October 29, 2001; 194(9): 1195 - 1206. [Abstract] [Full Text] [PDF]
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S. A. Pilon, M. P. Piechocki, and W.-Z. Wei Vaccination with Cytoplasmic ErbB-2 DNA Protects Mice from Mammary Tumor Growth Without Anti-ErbB-2 Antibody J. Immunol., September 15, 2001; 167(6): 3201 - 3206. [Abstract] [Full Text] [PDF]
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M. M. Soares, V. Mehta, and O. J. Finn Three Different Vaccines Based on the 140-Amino Acid MUC1 Peptide with Seven Tandemly Repeated Tumor-Specific Epitopes Elicit Distinct Immune Effector Mechanisms in Wild-Type Versus MUC1-Transgenic Mice with Different Potential for Tumor Rejection J. Immunol., June 1, 2001; 166(11): 6555 - 6563. [Abstract] [Full Text] [PDF]
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J.-P. H. Machiels, R. T. Reilly, L. A. Emens, A. M. Ercolini, R. Y. Lei, D. Weintraub, F. I. Okoye, and E. M. Jaffee Cyclophosphamide, Doxorubicin, and Paclitaxel Enhance the Antitumor Immune Response of Granulocyte/Macrophage-Colony Stimulating Factor-secreting Whole-Cell Vaccines in HER-2/neu Tolerized Mice Cancer Res., May 1, 2001; 61(9): 3689 - 3697. [Abstract] [Full Text]
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R. T. Reilly, J.-P. H. Machiels, L. A. Emens, A. M. Ercolini, F. I. Okoye, R. Y. Lei, D. Weintraub, and E. M. Jaffee The Collaboration of Both Humoral and Cellular HER-2/neu-targeted Immune Responses Is Required for the Complete Eradication of HER-2/neu-expressing Tumors Cancer Res., February 1, 2001; 61(3): 880 - 883. [Abstract] [Full Text]
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