To activate anti-tumor T lymphocyte responses in patients with breast cancer, this proposal targets the telomerase reverse transcriptase hTERT as a nearly universal tumor antigen in combination with the anti-CD25 mAb daclizumab to inhibit CD4+CD25+ negative regulatory T cells. hTERT is overexpressed by >95% of all breast carcinomas (although silent in most normal cells), and survival of hTERT+ tumor cells requires functionally active telomerase. Cytotoxic T lymphocytes (CTL) recognize peptides derived from hTERT and kill hTERT+ tumors cells of multiple histologies. Vaccination of cancer patients with hTERT peptide safely induces hTERT-specific CTL in blood and in tumor, associated in some patients with marked tumor necrosis. However, CD4+CD25+ regulatory T cells are found prominently in breast cancer and dampen immune responses, including anti-tumor T cell responses induced by vaccination. It is the central hypothesis of this proposal that hTERT-specific vaccination in combination with daclizumab to inhibit regulatory T cells in vivo will amplify anti-tumor immune responses to achieve clinically significant responses in patients with advanced breast cancer. To test this hypothesis, two clinical trials of hTERT peptide vaccination administered with daclizumab are proposed.
In AIM ONE, HLA-A2+ patients will receive daclizumab followed by vaccination with three hTERT peptides in adjuvant with GM-CSF. One of the peptides targets a high affinity hTERT CTL epitope and two heteroclitic peptides target novel low-affinity (""""""""cryptic"""""""") CTL epitopes derived from hTERT. This trial tests the safety and immunogenicity of the approach and determines the optimal dose of daclizumab to maximally and specifically disrupt Treg frequency and function.
In AIM TWO, patients will be randomized in a phase II study to receive hTERT peptide vaccine alone or vaccine plus daclizumab. This trial will determine the effect of daclizumab on the disruption of Treg function and the effect of daclizumab on the immunogenicity of vaccine as well as clinical response of patients with breast cancer. ? ?
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