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Vaccination with a HER2/neu peptide induces intra- and inter-antigenic epitope spreading in patients with early stage breast cancer

  • Elizabeth A. Mittendorf
    Affiliations
    Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC

    Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, Md
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  • Jennifer M. Gurney
    Affiliations
    Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC

    Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, Md
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  • Catherine E. Storrer
    Affiliations
    Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC

    Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, Md
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  • Craig D. Shriver
    Affiliations
    Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC

    Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, Md
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  • Sathibalan Ponniah
    Affiliations
    Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC

    Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, Md
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  • George E. Peoples
    Correspondence
    Reprint requests: George E. Peoples, MD, Department of Surgery, Walter Reed Army Medical Center, 6900 Georgia Ave, NW, Washington, DC 20307-5001.
    Affiliations
    Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC

    Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, Md
    Search for articles by this author

      Background

      We are conducting clinical vaccine trials with the HER2/neu peptide, E75, in patients with breast cancer. The purpose of this study was to demonstrate clonal expansion of E75-specific CD8+ T cells and to identify intra- and interantigenic epitope spreading.

      Method

      Pre- and postvaccination peripheral blood leukocyte samples (24 node positive [NP] and 20 node negative [NN]) from 44 vaccinated patients were analyzed. HLA-A2:Ig dimer molecules were loaded with the HER2 peptides, E75 or GP2, and were used with anti-TcR and CD8 antibodies to stain peripheral blood leukocyte immediately ex vivo and were analyzed with flow cytometry. In 8 randomly selected patients, dimers were loaded with the folate binding protein peptide E41 to evaluate for interantigenic epitope spreading.

      Results

      All patients with NP and 95% of the patients with NN showed E75-specific clonal expansion. Patients with NN showed more robust expansion. All patients with NP and 85% of the patients with NN showed evidence of intra-antigenic epitope that was spreading to GP2. However, patients with NN showed only moderate expansion to this subdominant epitope, which was not included in the immunizing mix. The degree of HER2/neu expression and disease stage impacted the ability to expand clonally E75- and GP2-specific CD8+ T cells. Evidence of interantigenic epitope spreading to E41 was shown in 63% of the patients who were tested.

      Conclusion

      Our data provide evidence for the induction of intra- and interantigenic epitope spreading that results from a single HER2/neu peptide vaccine even in early staged patients. The ability to raise immunity to multiple tumor antigens depends on both the degree of HER2/neu expression and the extent of disease. Epitope spreading is an essential element for the success of a peptide vaccine strategy.
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      References

        • Brossart P.
        • Wirths S.
        • Stuhler G.
        • Reichardt V.L.
        • Kanz L.
        • Brugger W.
        Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells.
        Blood. 2000; 96: 3102-3108
        • Disis M.L.
        • Gooley T.A.
        • Rinn K.
        • Davis D.
        • Piepkorn M.
        • Cheever M.A.
        • et al.
        Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.
        J Clin Oncol. 2002; 20: 2624-2632
        • Disis M.L.
        • Grabstein K.H.
        • Sleath P.R.
        • Cheever M.A.
        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
        • Kono K.
        • Takahashi A.
        • Sugai H.
        • Fujii H.
        • Choudhury A.R.
        • Kiesling R.
        • et al.
        Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer.
        Clin Cancer Res. 2002; 8: 3394-3400
        • Knutson K.L.
        • Schiffman K.
        • Cheever M.A.
        • Disis M.L.
        Immunization of cancer patients with HER-2/neu, HLA-A2 peptide, p369-377, results in short-lived peptide-specific immunity.
        Clin Cancer Res. 2002; 8: 1014-1018
        • Murray J.L.
        • Gillogly M.E.
        • Przepiorka D.
        • Brewer H.
        • Ibrahim N.K.
        • Booser D.J.
        • et al.
        Toxicity, immunogenicity, and induction of E75-specific tumor lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer.
        Clin Cancer Res. 2002; 8: 3407-3418
        • Zaks T.Z.
        • Rosenberg S.A.
        Immunization with a peptide epitope (p369-377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu + tumors.
        Cancer Res. 1998; 58: 4902-4908
        • Woll M.M.
        • Fisher C.M.
        • Ryan G.B.
        • Gurney J.M.
        • Storrer C.E.
        • Ioannides C.G.
        • et al.
        Direct measurement of peptide specific CD8+ T cells using HLA-A2:Ig dimer for monitoring the in vivo immune response to a HER2/neu vaccine in breast and prostate cancer patients.
        J Clin Immunol. 2004; 24: 449-461
        • Lotze M.T.
        • Slingluff C.L.
        • Sondak V.K.
        What’s new in immunotherapy for cancer treatment?.
        Contemp Surg. 2004; 12: 556-566
        • Vanderlugt C.H.
        • Miller S.D.
        Epitope spreading.
        Curr Opin Immunol. 1996; 8: 831-836
        • Sercarz E.E.
        Driver clones and determinant spreading.
        J Autoimmunol. 2000; 14: 275-277
        • Kim D.K.
        • Lee T.V.
        • Castilleja A.
        • Anderson B.W.
        • Peoples G.E.
        • Kudelka A.P.
        • et al.
        Folate binding protein peptide 191-199 presented on dendritic cells can stimulate CTL from ovarian and breast cancer patients.
        Anticancer Res. 1999; 19: 2907-2916
        • Peoples G.E.
        • Anderson B.W.
        • Lee T.V.
        • Murray J.L.
        • Kudelka A.P.
        • Wharton J.T.
        • et al.
        Vaccine implications of folate binding protein, a novel cytotoxic T lymphocyte-recognized antigen system in epithelial cancers.
        Clin Cancer Res. 1999; 5: 4214-4223
        • Apostolopoulos V.
        • McKenzie I.F.
        Cellular mucins.
        Crit Rev Immunol. 1994; 14: 293-309
        • Peoples G.E.
        • Goedegebuure P.S.
        • Smith R.
        • Linehan D.C.
        • Yoshino I.
        • Eberlein T.J.
        Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide.
        Proc Natl Acad Sci USA. 1995; 92: 432-436
        • Lee T.D.
        Distribution of HLA antigens in North American Caucasians, North American blacks and Orientals.
        in: Lee J. The HLA system. Springer-Verlag, New York1990: 141
        • Peoples G.E.
        • Gurney J.M.
        • Hueman M.T.
        • Woll M.M.
        • Ryan G.B.
        • Storrer C.E.
        • et al.
        Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients.
        J Clin Oncol. 2005; 23: 7536-7545
        • Anderson B.W.
        • Kudelka A.P.
        • Honda T.
        • Pollack M.S.
        • Gershenson D.M.
        • Gillogly M.A.
        • et al.
        Induction of determinant spreading and of Th1 responses by in vitro stimulation with Her-2 peptides.
        Cancer Immunol Immunother. 2000; 49: 459-468
        • Lehmann P.V.
        • Forsthuber T.
        • Miller A.
        • Sercarz E.E.
        Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen.
        Nature. 1992; 358: 155-157
        • Tien J.
        • Gregori S.
        • Adorini L.
        • Kaufman D.L.
        The frequency of high avidity T cells determines the hierarchy of determinant spreading.
        J Immunol. 2001; 166: 7144-7150
        • Tuohy V.K.
        • Yu M.
        • Yin L.
        • Kawezak J.A.
        • Kinkel R.P.
        Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis.
        J Exp Med. 1999; 189: 1033-1042
        • Ranieri E.
        • Kierstead L.S.
        • Zarour H.
        • Kirkwood J.M.
        • Lotze M.T.
        • Whiteside T.
        • et al.
        Dendritic cell/peptide cancer vaccines.
        Immunol Investig. 2000; 29: 121-125
        • Jonuleit H.
        • Giesecke-Tuettenberg A.
        • Tuting T.
        • Thurner-Schuler B.
        • Stuge T.B.
        • Paragnik L.
        • et al.
        A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in human following intranodal injection.
        Int J Cancer. 2001; 93: 243-251
        • Butterfield L.H.
        • Ribas A.
        • Disette V.B.
        • Amarnani S.M.
        • Vu H.T.
        • Oseguera D.
        • et al.
        Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma.
        Clin Cancer Res. 2003; 9: 998-1008
        • Kahn H.
        • Presta A.
        • Yang L.Y.
        • Blondal J.
        • Trudeau M.
        • Lickley L.
        • et al.
        Enumeration of circulating tumor cells in the blood of breast caner patients after filtration enrichment.
        Breast Cancer Res Treat. 2004; 86: 237-247
        • Meng S.
        • Debasish T.
        • Frenkel E.P.
        • Shete S.
        • Naftalis E.Z.
        • Huth J.F.
        • et al.
        Circulating tumor cells in patients with breast cancer dormancy.
        Clin Can Res. 2004; 10: 8152-8162