Abstract
Direct comparison and ranking of vaccine formulations in pre-clinical studies will expedite the identification of cancer vaccines for clinical trials. Two human ErbB-2 (Her-2) vaccines, naked DNA and whole cell vaccine, were tested side-by-side in wild type and Her-2 transgenic mice. Both vaccines can induce humoral and cellular immunity to the entire repertoire of Her-2 epitopes. Mice were electro-vaccinated i.m. with a mixture of pGM-CSF and pE2TM, the latter encodes Her-2 extracellular and transmembrane domains. Alternatively, mice were injected i.p. with human ovarian cancer SKOV3 cells that have amplified Her-2. In wild type mice, comparable levels of Her-2 antibodies (Ab) were induced by these two vaccines. However, T cell immunity and protection against Her-2+ tumors were superior in DNA vaccinated mice. In BALB Her-2 transgenic (Tg) mice, which were tolerant to Her-2, DNA and cell vaccines were administered after regulatory T cells (Treg) were removed by anti-CD25 mAb. Again, comparable levels of Her-2 Ab were induced, but DNA vaccines rendered greater anti-tumor activity. In B6xDR3 Her-2 Tg mice that expressed the autoimmune prone HLA-DR3 allele, higher levels of Her-2 Ab were induced by SKOV3 cell than by Her-2 DNA. But anti-tumor activity was still more profound in DNA vaccinated mice. Therefore, Her-2 DNA vaccine induced greater anti-tumor immunity than cell vaccine, whether mice were tolerant to Her-2 or susceptible to autoimmunity. Through such side-by-side comparisons in appropriate pre-clinical test systems, the more effective vaccine formulations will emerge as candidates for clinical trials.
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References
Christadoss P, Poussin M, Deng C (2000) Animal models of myasthenia gravis. Clin Immunol 94:75–87
Czerniecki BJ, Roses RE, Koski GK (2007) Development of vaccines for high-risk ductal carcinoma in situ of the breast. Cancer Res 67:6531–6534
de Vries RR, Huizinga TW, Toes RE (2005) Redefining the HLA and RA association: to be or not to be anti-CCP positive. J Autoimmun 25 Suppl:21–25
Disis ML, Grabstein KH, Sleath PR et al (1999) Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res 5:1289–1297
Dols A, Smith JW, Meijer SL et al (2003) Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther 14:1117–1123
Dyment DA, Ebers GC, Sadovnick AD (2004) Genetics of multiple sclerosis. Lancet Neurol 3:104–110
Harley JB, Moser KL, Gaffney PM et al (1998) The genetics of human systemic lupus erythematosus. Curr Opin Immunol 10:690–696
Hung MC, Lau YK (1999) Basic science of HER-2/neu: a review. Semin Oncol 26:51–59
Jacob J, Radkevich O, Forni G et al (2006) Activity of DNA vaccines encoding self or heterologous Her-2/neu in Her-2 or neu transgenic mice. Cell Immunol 240:96–106
Jacob JB, Kong YM, Meroueh C et al (2007) Control of Her-2 tumor immunity and thyroid autoimmunity by MHC and regulatory T cells. Cancer Res 67:7020–7027
Kiessling R, Wei WZ, Herrmann F et al (2002) Cellular immunity to the Her-2/neu protooncogene. Adv Cancer Res 85:101–144
King BL, Carter D, Foellmer HG et al (1992) Neu proto-oncogene amplification and expression in ovarian adenocarcinoma cell lines. Am J Pathol 140:23–31
Kong YM, Lomo LC, Motte RW et al (1996) HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis in transgenic mice: definitive association with HLA-DRB1*0301 (DR3) gene. J Exp Med 184:1167–1172
Lin KY, Guarnieri FG, Staveley-O’Carroll KF et al (1996) Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 56:21–26
Mahoney KH, Miller BE, Heppner GH (1985) FACS quantitation of leucine aminopeptidase and acid phosphatase on tumor-associated macrophages from metastatic and nonmetastatic mouse mammary tumors. J Leukoc Biol 38:573–585
Montgomery RB, Makary E, Schiffman K et al (2005) Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase. Cancer Res 65:650–656
Nanni P, Nicolson GL, De Giovanni C et al (2001) Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J Exp Med 194:1195–1205
Oldstone MB (2005) Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept. Curr Top Microbiol Immunol 296:1–17
Piechocki MP, Ho YS, Pilon S et al (2003) Human ErbB-2 (Her-2) transgenic mice: a model system for testing Her-2 based vaccines. J Immunol 171:5787–5794
Piechocki MP, Pilon SA, Wei WZ (2002) Quantitative measurement of anti-ErbB-2 antibody by flow cytometry and ELISA. J Immunol Methods 259:33–42
Pilon SA, Kelly C, Wei WZ (2003) Broadening of epitope recognition during immune rejection of ErbB-2-positive tumor prevents growth of ErbB-2-negative tumor. J Immunol 170:1202–1208
Pilon SA, Piechocki MP, Wei WZ (2001) Vaccination with cytoplasmic ErbB-2 DNA protects mice from mammary tumor growth without anti-ErbB-2 antibody. J Immunol 167:3201–3206
Reilly RT, Gottlieb MB, Ercolini AM et al (2000) HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice. Cancer Res 60:3569–3576
Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684
Rovero S, Amici A, Carlo ED et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133–5142
Sjogren S, Inganas M, Lindgren A et al (1998) Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 16:462–469
Slamon DJ, Clark GM, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182
Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712
Strauss G, Vignali DA, Schonrich G et al (1994) Negative and positive selection by HLA-DR3(DRw17) molecules in transgenic mice. Immunogenetics 40:104–108
Wei WZ, Jacob J, Radkevich-Brown O et al (2008) The “A, B and C” of Her-2 DNA vaccine development. Cancer Immunol Immunother 57(11):1711–1717
Wei WZ, Shi WP, Galy A et al (1999) Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA. Int J Cancer 81:748–754
Weinstein IB, Joe A, Felsher D (2008) Oncogene addiction. Cancer Res 68:3077–3080
Whittington PJ, Piechocki MP, Heng HH et al (2008) DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies. Cancer Res 68(18):7502–7511
Wolpoe ME, Lutz ER, Ercolini AM et al (2003) 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 171:2161–2169
Yakes FM, Chinratanalab W, Ritter CA et al (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62:4132–4141
Acknowledgments
This study was supported by NIH CA76340, CA125680 (WZW), Department of Defense W81XWH-04-1-0546 (WZW) and GM 58905-7 (IMSD). The authors wish to thank David Shim and Andi Cani for their technical assistance. We also thank Serene Lane and Laura Baksic for their expert care of the experimental animals.
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P. J. Whittington, O. Radkevich-Brown and J. B. Jacob have contributed equally to this work.
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Whittington, P.J., Radkevich-Brown, O., Jacob, J.B. et al. Her-2 DNA versus cell vaccine: immunogenicity and anti-tumor activity. Cancer Immunol Immunother 58, 759–767 (2009). https://doi.org/10.1007/s00262-008-0599-x
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DOI: https://doi.org/10.1007/s00262-008-0599-x