The goal is to use novel, yet straightforward DNA vaccines to overcome immune tolerance to tumor associated antigens, thus inducing anti-tumor immunity to provide long-term protection. Her-2 and DR5 death receptors are test vaccine antigens for controlling Her-2 positive and triple negative breast cancer (TNBC), respectively. Novel DNA constructs that combine heterologous and self antigen sequences will be tested as therapeutic cancer vaccines. To amplify vaccine activity, the effect of reducing natural and inducible regulatory T cells and intratumoral expression of immune modulating genes will be tested. To overcome immune tolerance to Her-2, we formulated DNA vaccines that express both human Her-2 and heterologous rat Neu sequences in separate plasmids or as single hybrid constructs that encode Her-2/neu fusion proteins. Candidate vaccines were tested in Her-2 transgenic (Tg) mice of BALB/c (BALB), BALB/c x C57BL/6 F1 (F1) or C57BL/6 (B6) background, which exhibited decreasing immune responsiveness to Her-2. Analysis of various cocktail or hybrid vaccines defined a requirement for particular combination of Her-2/Neu sequences to effectively prime immune effector cells in Her-2 Tg mice. We will test the hypothesis that vaccination with Her-2-neu hybrid DNA vaccine will reject established tumors and prevent tumor metastasis. Proapoptotic death receptor DR5 for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) will be the next vaccine antigen. Human DR5 immune sera induced in wild type mice triggered apoptosis of TNBC and inhibited their growth in vivo. Hybrid human-monkey DR5 vaccines are being constructed to incorporate highly homologous monkey DR5 sequence in human DR5 vaccines. To test vaccine activity in immune tolerant hosts, two human DR5 Tg mouse systems are being generated to mimic immune tolerance in humans. Vaccination with self antigen may trigger the conversion of na?ve CD4 T cells to induced Treg (iTreg). The role of iTreg in Her-2 vaccine response will be tested in mice deficient of TGF-? inducible early gene 1 (TIEG1) and the conversion of their na?ve CD4 T cells to iTreg is disabled. Further, the effect of TGF-? receptor inhibitor (TGF? RI) in blocking Treg activity and enhancing Her-2 immune response will be tested. To compliment DNA vaccination with minimal systemic immune modulation, we will exploit the vast antigen reservoir in the solid tumors by intratumoral expression of immune modulating genes. In situ immunization to tumor associated antigens and induction tumor regression will be assessed. Through the testing of these modalities, we aim to define the approach that can most readily be translated into a successful therapeutic vaccine Specifically, we will (1) determine the mechanisms that regulate immune responses to hybrid Her-2 DNA vaccines (2) test the hypothesis that hybrid pE2-NeuTM vaccination combined with complementary immune modulation will reject established tumors, and (3) test the immunogenicity and anti-tumor activity of hDR5 DNA vaccines. The proposed hybrid vaccines complimented with local expression of immune modulating genes and inhibition of Treg, can be expected to achieve complete response with long term immune memory. Importantly, Her-2 and DR5 are expressed by multiple cancer types, thus the impact will reach far beyond breast cancer.

Public Health Relevance

The ultimate goal of cancer immunotherapy is to treat or prevent cancer by vaccination. The proposed project will test novel DNA vaccines targeting two critical molecules: Her-2 which mediates tumor cell survival and TRAIL death receptor DR5 which mediates tumor cell apoptosis. Strong preliminary data is presented to support the immunogenicity and potential efficacy of vaccines targeting these two molecules. A series of experiments are proposed to elucidate the mechanism of action and to define vaccination regimen that can most readily be translated into a successful therapeutic vaccine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076340-15
Application #
8594112
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
1997-12-04
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
15
Fiscal Year
2014
Total Cost
$1
Indirect Cost
Name
Wayne State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Veenstra, Jesse J; Gibson, Heather M; Littrup, Peter J et al. (2014) Cryotherapy with concurrent CpG oligonucleotide treatment controls local tumor recurrence and modulates HER2/neu immunity. Cancer Res 74:5409-20
Peng, Dong-Jun; Zeng, Minghui; Muromoto, Ryuta et al. (2011) Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth. J Immunol 186:5638-47
Jacob, Jennifer B; Quaglino, Elena; Radkevich-Brown, Olga et al. (2010) Combining human and rat sequences in her-2 DNA vaccines blunts immune tolerance and drives antitumor immunity. Cancer Res 70:119-28
Radkevich-Brown, Olga; Piechocki, Marie P; Back, Jessica B et al. (2010) Intratumoral DNA electroporation induces anti-tumor immunity and tumor regression. Cancer Immunol Immunother 59:409-17
Norell, Hakan; Poschke, Isabel; Charo, Jehad et al. (2010) Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial. J Transl Med 8:53
Jacob, Jennifer B; Kong, Yi-chi M; Nalbantoglu, Ilke et al. (2009) Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity. J Immunol 182:5873-81
Whittington, Paula J; Radkevich-Brown, Olga; Jacob, Jennifer B et al. (2009) Her-2 DNA versus cell vaccine: immunogenicity and anti-tumor activity. Cancer Immunol Immunother 58:759-67
Radkevich-Brown, Olga; Jacob, Jennifer; Kershaw, Michael et al. (2009) Genetic regulation of the response to Her-2 DNA vaccination in human Her-2 transgenic mice. Cancer Res 69:212-8
Whittington, Paula J; Piechocki, Marie P; Heng, Henry H et al. (2008) DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies. Cancer Res 68:7502-11

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