Molecules essential for tumor growth and development represent promising targets for novel immunotherapy of cancer, yet host immunosuppressive factors impose major challenges for translating this hypothesis into clinical success. This proposal addresses these obstacles in breast cancer by combining a novel vaccine against the human telomerase reverse transcriptase (hTERT) and survivin in combination with anti-CD25 antibody daclizumab in patients with hormone receptor positive (HR+) metastatic disease. hTERT and survivin are expressed in >90% of human breast tumors but rarely in normal cells, and each critically contributes to the malignant phenotype. We have shown that cytotoxic T lymphocytes recognize peptides derived from hTERT and survivin and kill tumors cells expressing these proteins across a wide range of histologies. During the previous funding period, we vaccinated patients with metastatic breast cancer with a single hTERT peptide and demonstrated the induction of hTERT- specific CD8+ T cells in both blood and tumor, associated with major alterations in the tumor micro- environment and increased overall survival. We also found that immunosuppressive regulatory T cells (Tregs) are abundant in breast cancer and in a pilot clinical study, a single infusion of the anti-CD25 monoclonal antibody (mAb) daclizumab resulted in prolonged depletion of CD4+ Foxp3+ CD25+ Tregs in patients at a level not previously achievable. We hypothesize that a vaccine against hTERT and survivin in combination with daclizumab to deplete regulatory T cells can induce anti-tumor immune responses and offer clinical benefit for patients with HR+ metastatic breast cancer. To test this hypothesis, we propose two randomized clinical trials employing a second-generation vaccine already approved for investigation by FDA and involving multiple hTERT and survivin peptides in adjuvant, GM-CSF, and the CRM197-containing pneumococcal vaccine Prevnar (PCV), the latter a novel approach to induce T cell help.
In Aim One, HLA-A2+ patients with HR+ metastatic breast cancer with progression through first or subsequent hormonal therapy for metastatic disease will be randomized to receive next appropriate hormonal therapy and hTERT/survivin/PCV vaccination with or without daclizumab to assess the effect of Treg depletion on the immunogenicity of the vaccine.
In Aim Two, HLA-A2+ patients with HR+ metastatic disease and progression through first hormonal therapy for metastatic disease will receive second-line hormonal therapy with or without vaccine. The move from Aim One to Aim Two, therefore, represents a smooth and justified extension of our approach to a larger cohort of healthier and less heavily pretreated patients with HR+ metastatic disease. In both aims, immunological monitoring of T cell responses and Treg modulation will be performed to provide insights into immune mechanisms related to the observed clinical effects. The goal is to establish an immunologically potent vaccine that offers clinical benefit for patients with HR+ metastatic breast cancer.

Public Health Relevance

We aim to determine the immunological and clinical impact of a novel vaccine targeting hTERT and survivin with and without daclizumab in patients with metastatic hormone receptor positive breast cancer. All patients in the proposed clinical trials will also receive the next appropriate hormone therapy per standard of care. The long-term goal is to develop an immune-based therapy that offers clinical benefit to patients with hormone receptor positive breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111377-07
Application #
8296633
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Song, Min-Kyung H
Project Start
2004-12-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$307,381
Indirect Cost
$115,268
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Vonderheide, Robert H (2007) Universal tumor antigens for cancer vaccination: targeting telomerase for immunoprevention. Discov Med 7:103-8
Vonderheide, Robert H (2007) Prospect of targeting the CD40 pathway for cancer therapy. Clin Cancer Res 13:1083-8
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