Annals of Surgical Oncology

, Volume 13, Issue 8, pp 1085–1098

Investigating the Combination of Trastuzumab and HER2/neu Peptide Vaccines for the Treatment of Breast Cancer

  • Elizabeth A. Mittendorf
  • Catherine E. Storrer
  • Craig D. Shriver
  • Sathibalan Ponniah
  • George E. Peoples
Article

DOI: 10.1245/ASO.2006.03.069

Cite this article as:
Mittendorf, E.A., Storrer, C.E., Shriver, C.D. et al. Ann Surg Oncol (2006) 13: 1085. doi:10.1245/ASO.2006.03.069

Abstract

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 μg/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 μg/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 μg/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.

Keywords

Breast cancerHER2/neuImmunotherapyTrastuzumabPeptide vaccine

Copyright information

© The Society of Surgical Oncology, Inc. 2006

Authors and Affiliations

  • Elizabeth A. Mittendorf
    • 1
    • 2
  • Catherine E. Storrer
    • 2
  • Craig D. Shriver
    • 1
    • 2
  • Sathibalan Ponniah
    • 2
  • George E. Peoples
    • 1
    • 2
  1. 1.Clinical Breast Care Project, Department of SurgeryWalter Reed Army Medical CenterWashingtonUSA
  2. 2.National Naval Medical Center, Henry M. Jackson Foundation for the Advancement of Military MedicineClinical Breast Care Project Immunology & Research CenterBethesdaUSA