Abstract
The gene for HER2/neu is overexpressed in 30–40% of breast and ovarian cancers, and this overexpression correlates with increased metastasis and poor prognosis. The HER2/neu gene product, a transmembrane protein kinase member of the EGF receptor family, has significant potential as a tumor antigen for vaccination. We inserted the sequence for neu into a novel plasmid called ELVIS containing a Sindbis virus replicon that reproduces multiple copies of mRNA. Mice vaccinated one time intramuscularly demonstrated a strong antibody response against A2L2, a murine breast cancer cell line transfected to express neu. Vaccinated mice challenged in the mammary fatpad with A2L2 had reduced tumor incidence and reduced tumor mass compared to mice challenged with tumor cells lacking the neu insert. Intradermal vaccination was also protective and required 80% less plasmid for a similar level of protection. Vaccination reduced the incidence of lung metastasis from mammary fatpad tumors and reduced the number of lung metastases resulting from intravenous injection of A2L2 cells. Cytotoxic T lymphocytes cultures of immune spleen cells with P815-neu cells produced high levels of interferon-γ indicating an antigen-specific Th1-type immune response resulting from the vaccination. In a spontaneous breast tumor model using neu transgenic mice, vaccination with ELVIS-neu protected against development of spontaneous breast tumors. Our preclinical data indicate that therapeutic vaccination of patients with ELVIS-neu may reduce metastasis from HER2/neu-expressing breast and ovarian tumors. Cancer Gene Therapy (2001) 8, 259–268
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References
Fornier M, Munster P, Seidman AD . Update on the management of advanced breast cancer Oncology 1999; 13:: 647–658
Disis ML, Grabstein KH, Sleath PR, Cheever MA . 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 1999; 5:: 1289–1297
Ross JS, Fletcher JA . The HER-2/neu oncogene: prognostic factor, predictive factor and target for therapy Semin Cancer Biol 1999; 9:: 125–138
Weiner LM . An overview of monoclonal antibody therapy of cancer Semin Oncol 1999; 26:: 41–50
Conry RM, LoBuglio AF, Curiel DT . Polynucleotide-mediated immunization therapy of cancer Semin Oncol 1996; 23:: 135–147
Gurunathan S, Klinman DM, Seder RA . DNA vaccines: immunology, application, and optimization Annu Rev Immunol 2000; 18:: 927–974
Leitner WW, Ying H, Driver DA, Dubensky TW, Restifo NP . Enhancement of tumor-specific immune response with plasmid DNA replicon vectors Cancer Res 2000; 60:: 51–55
Dubensky TW Jr, Polo JM, Liu MA . Live virus vaccines: something old, something new, something borrowed Nat Med 1998; 4:: 1357–1358
Pushko P, Bray M, Ludwig GV, et al . Recombinant RNA replicons derived from attenuated Venezuelan equine encephalitis virus protect guinea pigs and mice from Ebola hemorrhagic fever virus Vaccine 2000; 19:: 142–153
Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ . Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease Proc Natl Acad Sci USA 1992; 89:: 10578–10582
Miller FR, Miller BE, Heppner GH . Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability Invasion Metastasis 1983; 3:: 22–31
Mukhopadhyay R, Theriault RL, Price JE . Increased levels of 6 integrins are associated with the malignant phenotype of human breast cancer cells Clin Exp Metastasis 1999; 17:: 325–332
Hariharan MJ, Driver DA, Townsend K, et al . DNA immunization against herpes simplex virus: enhanced efficacy using a Sindbis virus-based vector J Virol 1998; 72:: 950–958
Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P . Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene Cell 1988; 54:: 105–115
Klein C, Bueler H, Mulligan RC . Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines J Exp Med 2000; 191:: 1699–1708
van Elsas A, Hurwitz AA, Allison JP . Combination immunotherapy of B16 melanoma using anticytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)–producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation J Exp Med 1999; 190:: 355–366
Wolff JA, Malone RW, Williams P, et al . Direct gene transfer into mouse muscle in vivo Science 1990; 247:: 1465–1468
Chattergoon M, Boyer J, Weiner DB . Genetic immunization — a new era in vaccine and immune therapeutics FASEB J 1997; 11:: 753–763
Chen Y, Hu D, Eling DJ, Robbins J, Kipps TJ . DNA vaccines encoding full-length or truncated neu induce protective immunity against neu-expressing mammary tumors Cancer Res 1998; 58:: 1965–1971
Amici A, Smorlesi A, Noce G, et al . DNA vaccination with full-length or truncated neu induces protective immunity against the development of spontaneous mammary tumors in HER-2/neu transgenic mice Gene Ther 2000; 7:: 703–706
Acknowledgements
We thank Walter Pagel, Department of Scientific Publications, for careful review of this manuscript and Craig A. Mullen, Department of Pediatrics, for assistance with the CTL cultures. This research was supported by the US Army Medical Research and Material Command, Department of Defense Breast Cancer Research Program, BC980071 and the W. M. Keck Center for Cancer Gene Therapy; The Breast Cancer Research Program; The Kleberg Fund for New and Innovative Research; and the Physicians Referral Service of The University of Texas M. D. Anderson Cancer Center and CA16672 from the National Cancer Institute.
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Lachman, L., Rao, XM., Kremer, R. et al. DNA vaccination against neu reduces breast cancer incidence and metastasis in mice. Cancer Gene Ther 8, 259–268 (2001). https://doi.org/10.1038/sj.cgt.7700300
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DOI: https://doi.org/10.1038/sj.cgt.7700300
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