In vitro stimulation of ovarian tumour-associated lymphocytes with a peptide derived from HER2/neu induces cytotoxicity against autologous tumour

D. C. Linehan, G. E. Peoples, D. T. Hess, I. C. Summerhayes, A. S. Parikh, P. S. Goedegebuure, T. J. Eberlein

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15 Scopus citations


The proto-oncogene HER2/neu encodes for a 185 kDa transmembrane protein with extensive homology to the epidermal growth factor (EGF) receptor. We have previously shown a correlation between HER2/neu expression and the level of in vitro cytotoxicity of tumour-associated lymphocytes (TAL) versus autologous tumour. In addition, we have recently demonstrated that tumour-associated cytotoxic T-lymphocytes (CTL) from ovarian and breast cancer patients can recognize a HER2/neu derived peptide epitope when presented in the context of HLA-A2. Since repeated tumour stimulation of CTL enhances both proliferation and cytotoxicity against autologous tumour, we hypothesized that repeated peptide antigen stimulation would have a similar effect. To be therapeutically useful, the peptide antigen must meet the following conditions: (1) the peptide must be immunogenic and cause a proliferation of CTL to adequate therapeutic numbers, and (2) the peptide-specific CTL which are generated must be cytotoxic against autologous tumour. To test our hypothesis, T-lymphocytes isolated from the ascites of four consecutive HER2/neu+ ovarian cancer patients were initially stimulated with solid phase anti-CD3 antibody and divided into three groups: (1) treatment with recombinant interleukin-2 (IL-2) alone, (2) IL-2 plus weekly stimulation with irradiated autologous tumour cells, and (3) IL-2 plus weekly stimulation with a HER2/neu derived peptide. Peptide-stimulated and tumour-stimulated CTL showed similar increases in proliferation with both groups consistently reaching therapeutic numbers. Peptide-stimulated CTL demonstrated significantly enhanced cytotoxicity against autologous tumour in 4-h chromium release assays as compared to the IL-2 alone group. This cytotoxicity appeared to be HLA-A2 restricted as peptide-stimulated CTL from HLA-A2+ patients had significantly increased cytotoxicity against allogeneic HLA-A2+ tumour cells as compared with allogeneic HLA-A2 tumour cells. In addition, the cytotoxicity of peptide-stimulated CTL against autologous tumour was blocked with an anti-HLA-A2 monoclonal antibody, BB7.2. These findings have potential clinical applicability in that an unlimited amount of synthetic peptide could be available for repeated CTL stimulation when culturing cells for adoptive immunotherapy. This could be especially beneficial when adequate amounts of tumour cells for stimulation are unavailable. In addition, the identification of tumour-associated antigens which can be recognized by autologous CTL may ultimately be useful in the development of antitumour vaccine therapy.

Original languageEnglish
Pages (from-to)41-49
Number of pages9
JournalSurgical Oncology
Issue number1
StatePublished - 1995


  • HER2/neu
  • HLA-A2
  • ovarian cancer
  • peptide
  • tumour-associated lymphocytes


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