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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111377-03
Application #
7256893
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2005-07-21
Project End
2009-06-30
Budget Start
2007-07-19
Budget End
2009-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$316,994
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Vonderheide, Robert H; Domchek, Susan M; Clark, Amy S (2017) Immunotherapy for Breast Cancer: What Are We Missing? Clin Cancer Res 23:2640-2646
Rech, Andrew J; Mick, Rosemarie; Martin, Sunil et al. (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 4:134ra62
Rech, Andrew J; Mick, Rosemarie; Kaplan, David E et al. (2010) Homeostasis of peripheral FoxP3(+) CD4 (+) regulatory T cells in patients with early and late stage breast cancer. Cancer Immunol Immunother 59:599-607
Golovina, Tatiana N; Vonderheide, Robert H (2010) Regulatory T cells: overcoming suppression of T-cell immunity. Cancer J 16:342-7
Rech, Andrew J; Vonderheide, Robert H (2009) Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci 1174:99-106
Vonderheide, Robert H (2008) Prospects and challenges of building a cancer vaccine targeting telomerase. Biochimie 90:173-80
Beatty, Gregory L; Vonderheide, Robert H (2008) Telomerase as a universal tumor antigen for cancer vaccines. Expert Rev Vaccines 7:881-7
Chen, Dih-Yih; Vance, Barbara A; Thompson, Lara B S et al. (2007) Differential lysis of tumors by polyclonal T cell lines and T cell clones specific for hTERT. Cancer Biol Ther 6:1991-6
Domchek, Susan M; Recio, Adri; Mick, Rosemarie et al. (2007) Telomerase-specific T-cell immunity in breast cancer: effect of vaccination on tumor immunosurveillance. Cancer Res 67:10546-55
Vonderheide, Robert H (2007) Universal tumor antigens for cancer vaccination: targeting telomerase for immunoprevention. Discov Med 7:103-8

Showing the most recent 10 out of 11 publications