Investigating the combination of trastuzumab and HER2/neu peptide vaccines for the treatment of breast cancer

Ann Surg Oncol. 2006 Aug;13(8):1085-98. doi: 10.1245/ASO.2006.03.069. Epub 2006 Jul 24.


Background: Trastuzumab, an anti-HER2/neu monoclonal antibody, is thought to promote HER2/neu receptor internalization and/or turnover. This study was designed to investigate the kinetics of trastuzumab treatment on tumor cells with varying levels of HER2/neu expression and to determine the effect of trastuzumab on HER2/neu-specific cytotoxic T lymphocyte-mediated lysis.

Methods: Three cell lines with varying levels of HER2/neu expression were incubated with varying doses of trastuzumab at multiple time points. Trastuzumab binding and HER2/neu expression were determined. Peripheral blood mononuclear cells from three HLA-A2(+) healthy donors and four E75 peptide-vaccinated patients were stimulated with HER2/neu-derived peptides and tested in standard chromium release cytotoxicity assays with HER2/neu(+) tumor cells pretreated with trastuzumab.

Results: Treatment of tumor cells with 10 microg/mL of trastuzumab in an overnight incubation resulted in saturation of cell-surface HER2/neu receptors. At higher doses, trastuzumab staining and HER2/neu expression decreased in a time-dependent manner. Pretreatment of tumor cells with trastuzumab resulted in increases in specific cytotoxicity by peptide-stimulated cytotoxic T lymphocytes from HLA-A2(+) donors over untreated cells by an average of 5.6% and 15.3% (P = .0002) for doses of 10 and 50 microg/mL, respectively. In similar experiments involving peripheral blood mononuclear cells obtained from immunized patients, the average specific cytotoxicity for untreated cells was 34.2% +/- 1.3% vs. 40.6% +/- 2.5% (P = .035) and 40.7% +/- 1.6% (P = .0005) for those treated with 10 and 50 microg/mL, respectively.

Conclusions: Our data suggest that pretreatment of breast cancer cells with trastuzumab induces turnover of the HER2/neu protein and enhanced killing by HER2/neu peptide-stimulated CTLs. This increased lysis occurs regardless of the degree of HER2/neu expression and seems more pronounced in vaccinated patients. These findings support further investigation into the use of combination immunotherapy with trastuzumab and HER2/neu peptide-based vaccines.

Publication types

  • Clinical Trial
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Breast Neoplasms / immunology
  • Breast Neoplasms / therapy*
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines*
  • Chromium / metabolism
  • Dendritic Cells / immunology
  • Epitopes / immunology
  • Female
  • Humans
  • Peptide Fragments / immunology*
  • Peptide Fragments / therapeutic use
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • Trastuzumab
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Cancer Vaccines
  • Epitopes
  • HER-2 peptide E75 (369-377), human
  • HER2-neu-derived peptide (654-662)
  • Peptide Fragments
  • Chromium
  • Receptor, ErbB-2
  • Trastuzumab