Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 11/2008

01-11-2008 | Symposium Paper

The “A, B and C” of Her-2 DNA vaccine development

Authors: Wei-Zen Wei, Jennifer Jacob, Olga Radkevich-Brown, Paula Whittington, Yi-chi M. Kong

Published in: Cancer Immunology, Immunotherapy | Issue 11/2008

Login to get access

Abstract

Introduction

The development of Her-2 DNA vaccine has progressed through three phases that can be categorized as phase “A”: the pursuit of Her-2 as a tumor-associated “antigen”, phase “B”: tilting the “balance” between tumor immunity and autoimmunity and phase “C”: the on-going “clinical trials”.

Materials and methods

In phase “A”, a panel of human ErbB-2 or Her-2 plasmids were constructed to encode non-transforming Her-2 derivatives. The immunogenicity and anti-tumor activity of Her-2 DNA vaccines were tested in human Her-2 transgenic mice with or without the depletion of regulatory T cells (Tregs). However, Treg depletion or other immune modulating regimens may increase the risk of autoimmunity. In phase “B”, the balance between tumor immunity and autoimmunity was assessed by monitoring the development of experimental autoimmune thyroiditis (EAT). To test the efficacy of Her-2 DNA vaccines in cancer patients, clinical trials have been initiated in phase “C”.

Results and conclusions

Significant anti-Her-2 and anti-tumor activity was observed when Her-2 transgenic mice were electro-vaccinated after Treg depletion. Susceptibility to EAT was also enhanced by Treg depletion and there was mutual amplification between Her-2 immunity and EAT development. Although Tregs regulate both EAT and Her-2 immunity, their effector mechanisms may differ. It may be possible to amplify tumor immunity with improved strategies that can by-pass undue autoimmunity. Critical information will be revealed in the next decade to expedite the development of cancer vaccines.
Literature
1.
Hung MC, Lau YK (1999) Basic science of HER-2/neu: a review. Semin Oncol 26(12 Suppl 4):51–59PubMed
2.
Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRef
3.
Ben-Levy R, Paterson HF, Marshall CJ et al (1994) A single autophosphorylation site confers oncogenicity tothe Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway. EMBO J 13:3302–3311PubMed
4.
Wada T, Qian XL, Greene MI (1990) Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell 61:1339–1347PubMedCrossRef
5.
Wei WZ, Shi WP, Galy A et al (1999) Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA. Int J Cancer 81:748–754PubMedCrossRef
6.
Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRef
7.
Pilon SA, Piechocki MP, Wei WZ (2001) Vaccination with cytoplasmic ErbB-2 DNA protects mice from mammary tumor growth without anti-ErbB-2 antibody. J Immunol 167:3201–3206PubMed
8.
Kiessling R, Wei WZ, Herrmann F et al (2002) Cellular immunity to the Her-2/neu protooncogene. Adv Cancer Res 85:101–144PubMedCrossRef
9.
Piechocki MP, Pilon SA, Wei WZ (2002) Quantitative measurement of anti-ErbB-2 antibody by flow cytometry and ELISA. J Immunol Methods 259:33–42PubMedCrossRef
10.
Pilon SA, Kelly C, Wei WZ (2003) Broadening of epitope recognition during immune rejection of ErbB-2-positive tumor prevents growth of ErbB-2-negative tumor. J Immunol 170:1202–1208PubMed
11.
Piechocki MP, Ho YS, Pilon S et al (2003) Human ErbB-2 (Her-2) transgenic mice: a model system for testing Her-2 based vaccines. J Immunol 171:5787–5794PubMed
12.
Lindencrona JA, Preiss S, Kammertoens T et al (2004) CD4+ T cell-mediated HER-2/neu-specific tumor rejection in the absence of B cells. Int J Cancer 109:259–264PubMedCrossRef
13.
Wei WZ, Morris GP, Kong YM (2004) Anti-tumor immunity and autoimmunity: a balancing act of regulatory T cells. Cancer Immunol Immunother 53:73–78PubMedCrossRef
14.
Miller F, Jones RF, Jacob J et al (2004) From breast cancer immunobiology to her-2 DNA vaccine and autoimmune sequelae. Breast Dis 20:43–51PubMed
15.
Wei WZ, Jacob JB, Zielinski JF et al (2005) Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4+ CD25+ regulatory T cell-depleted mice. Cancer Res 65:8471–8478PubMedCrossRef
16.
Jacob J, Radkevich O, Forni G et al (2006) Activity of DNA vaccines encoding self or heterologous Her-2/neu in Her-2 or neu transgenic mice. Cell Immunol 240:96–106PubMedCrossRef
17.
Piechocki MP, Pilon SA, Wei WZ (2001) Complementary antitumor immunity induced by plasmid DNA encoding secreted and cytoplasmic human ErbB-2. J Immunol 167:3367–3374PubMed
18.
Jacob JB, Kong YM, Meroueh C et al (2007) Control of Her-2 tumor immunity and thyroid autoimmunity by MHC and regulatory T cells. Cancer Res 67:7020–7027PubMedCrossRef
19.
Ursini-Siegel J, Schade B, Cardiff RD et al (2007) Insights from transgenic mouse models of ERBB2-induced breast cancer. Nat Rev Cancer 7:389–397PubMedCrossRef
20.
Rovero S, Amici A, Carlo ED et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133–5142PubMed
21.
Piechocki MP, Yoo GH, Dibbley SK et al (2007) Breast cancer expressing the activated HER2/neu is sensitive to gefitinib in vitro and in vivo and acquires resistance through a novel point mutation in the HER2/neu. Cancer Res 67:6825–6843PubMedCrossRef
22.
Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218PubMed
23.
Reilly RT, Gottlieb MB, Ercolini AM et al (2000) HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice. Cancer Res 60:3569–3576PubMed
24.
Singh R, Paterson Y (2007) In the FVB/N HER-2/neu transgenic mouse both peripheral and central tolerance limit the immune response targeting HER-2/neu induced by Listeria monocytogenes-based vaccines. Cancer Immunol Immunother 56:927–938PubMedCrossRef
25.
Bos R, van DS, van HT et al (2005) Expression of a natural tumor antigen by thymic epithelial cells impairs the tumor-protective CD4+ T-cell repertoire. Cancer Res 65:6443–6449PubMedCrossRef
26.
Gallo P, Dharmapuri S, Nuzzo M et al (2005) Xenogeneic immunization in mice using HER2 DNA delivered by an adenoviral vector. Int J Cancer 113:67–77PubMedCrossRef
27.
Pupa SM, Iezzi M, Di CE et al (2005) Inhibition of mammary carcinoma development in HER-2/neu transgenic mice through induction of autoimmunity by xenogeneic DNA vaccination. Cancer Res 65:1071–1078PubMed
28.
Tegerstedt K, Lindencrona JA, Curcio C et al (2005) A single vaccination with polyomavirus VP1/VP2Her2 virus-like particles prevents outgrowth of HER-2/neu-expressing tumors. Cancer Res 65:5953–5957PubMedCrossRef
29.
Huang W, Kukes GD (1999) Hashimoto’s thyroiditis: an organ-specific autoimmune disease-pathogenesis and recent developments. Lab Invest 79:1175–1180PubMed
30.
Canonica GW, Cosulich ME, Croci R et al (1984) Thyroglobulin-induced T-cell in vitro proliferation in Hashimoto’s thyroiditis: identification of the responsive subset and effect of monoclonal antibodies directed to Ia antigens. Clin Immunol Immunopathol 32:132–141PubMedCrossRef
31.
Vaidya B, Kendall-Taylor P, Pearce SHS (2002) Genetics of endocrine disease: the genetics of autoimmune thyroid disease. J Clin Endocrinol Metab 87:5385–5397PubMedCrossRef
32.
Kong YM, Lomo LC, Motte RW et al (1996) HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis in transgenic mice: definitive association with HLA-DRB1*0301 (DR3) gene. J Exp Med 184:1167–1172PubMedCrossRef
33.
Kong YM, David CS, Lomo LC et al (1997) Role of mouse and human class II transgenes in susceptibility to and protection against mouse autoimmune thyroiditis. Immunogenetics 46:312–317PubMedCrossRef
34.
Vladutiu AO, Rose NR (1971) Autoimmune murine thyroiditis: relation to histocompatibility (H-2) type. Science 174:1137–1139PubMedCrossRef
35.
36.
Levin L, Ban Y, Concepcion E et al (2004) Analysis of HLA genes in families with autoimmune diabetes and thyroiditis. Hum Immunol 65:640–647PubMedCrossRef
37.
Esquivel PS, Rose NR, Kong YM (1977) Induction of autoimmunity in good and poor responder mice with mouse thyroglobulin and lipopolysaccharide. J Exp Med 145:1250–1263PubMedCrossRef
38.
Elrehewy M, Kong YM, Giraldo AA et al (1981) Syngeneic thyroglobulin is immunogenic in good responder mice. Eur J Immunol 11:146–151PubMedCrossRef
39.
McNeel DG, Knutson KL, Schiffman K et al (2003) Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant. J Clin Immunol 23:62–72PubMedCrossRef
40.
Disis ML, Rinn K, Knutson KL et al (2002) Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu-overexpressing cancers. Blood 99:2845–2850PubMedCrossRef
41.
42.
Kong YM, Giraldo AA, Waldmann H et al (1989) Resistance to experimental autoimmune thyroiditis: L3T4+ cells as mediators of boththyroglobulin-activated and TSH-induced suppression. Clin Immunol Immunopathol 51:38–54PubMedCrossRef
43.
Sakaguchi S, Sakaguchi N, Asano M et al (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMed
44.
Morris GP, Chen L, Kong YM (2003) CD137 signaling interferes with activation and function of CD4+CD25+ regulatory T cells in induced tolerance to experimental autoimmune thyroiditis. Cell Immunol 226:20–29PubMedCrossRef
45.
Morris GP, Yan Y, David CS et al (2005) H2A- and H2E-derived CD4+CD25+ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis. J Immunol 174:3111–3116PubMed
46.
Morris GP, Kong YM (2006) Interference with CD4(+)CD25(+) T-cell-mediated tolerance to experimental autoimmune thyroiditis by glucocorticoid-induced tumor necrosis factor receptor monoclonal antibody. J Autoimmun 26:24–31PubMedCrossRef
47.
Maker AV, Attia P, Rosenberg SA (2005) Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 175:7746–7754PubMed
48.
Blansfield JA, Beck KE, Tran K et al (2005) Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593–598PubMedCrossRef
49.
Attia P, Phan GQ, Maker AV et al (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043–6053PubMedCrossRef
50.
Maker AV, Phan GQ, Attia P et al (2005) Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 12:1005–1016PubMedCrossRef
51.
Robinson MR, Chan CC, Yang JC et al (2004) Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother 27:478–789PubMedCrossRef
52.
Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377PubMedCrossRef
53.
Rose NR, Bacon LD, Sundick RS et al (1977) Genetic regulation in autoimmune thyroiditis. In: Talal N (ed) Autoimmunity: genetics, immunologic, virologic, and clinical aspects. Academic Press, New York, pp 63–87
Metadata
Title
The “A, B and C” of Her-2 DNA vaccine development
Authors
Wei-Zen Wei
Jennifer Jacob
Olga Radkevich-Brown
Paula Whittington
Yi-chi M. Kong
Publication date
01-11-2008
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 11/2008
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-008-0464-y

Other articles of this Issue 11/2008

Cancer Immunology, Immunotherapy 11/2008 Go to the issue

Original Article

Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer

Symposium Paper

Optimized DNA vaccines to specifically induce therapeutic CD8 T cell responses against autochthonous breast tumors

Symposium Paper

Development of a dendritic cell-based vaccine for chronic lymphocytic leukemia

Original Article

Combination of two fiber-mutant adenovirus vectors, one encoding the chemokine FKN and another encoding cytokine interleukin 12, elicits notably enhanced anti-tumor responses

Symposium Paper

Oncoantigens as anti-tumor vaccination targets: the chance of a lucky strike?

Symposium Paper

Progress in Vaccination against Cancer 2007 (PIVAC 7)
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits