Virus-like particle display of HER2 induces potent anti-cancer responses

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ABSTRACT

Overexpression of human epidermal growth factor receptor-2 (HER2) occurs in 20–30% of invasive breast cancers. Monoclonal antibody therapy is effective in treating HER2-driven mammary carcinomas, but its utility is limited by high costs, side effects and development of resistance. Active vaccination may represent a safer, more effective and cheaper alternative, although the induction of strong and durable autoantibody responses is hampered by immune-tolerogenic mechanisms. Using a novel virus-like particle (VLP) based vaccine platform we show that directional, high-density display of human HER2 on the surface of VLPs, allows induction of therapeutically potent anti-HER2 autoantibody responses. Prophylactic vaccination reduced spontaneous development of mammary carcinomas by 50%-100% in human HER2 transgenic mice and inhibited the growth of HER2-positive tumors implanted in wild-type mice. The HER2-VLP vaccine shows promise as a new cost-effective modality for prevention and treatment of HER2-positive cancer. The VLP platform may represent an effective tool for development of vaccines against other non-communicable diseases.

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Most cited references 67

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Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

Dennis J Slamon, Brian Leyland-Jones, Steven Shak … (2001)

The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

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Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

D Slamon, G G Clark, S C-S Wong … (1987)

The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

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Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns.

Martin Bachmann, Gary T Jennings (2010)

Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens that can be mimicked by vaccine delivery systems are their size, shape and surface molecule organization. In addition, pathogen-associated molecular patterns can be used to induce innate immune responses that promote adaptive immunity. In this Review, we discuss the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy.

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Author and article information

Journal

Journal ID (nlm-ta): Oncoimmunology

Journal ID (iso-abbrev): Oncoimmunology

Journal ID (publisher-id): KONI

Journal ID (publisher-id): koni20

Title: Oncoimmunology

Publisher: Taylor & Francis

ISSN (Print): 2162-4011

ISSN (Electronic): 2162-402X

Publication date Collection: 2018

Publication date (Electronic): 5 January 2018

Publication date PMC-release: 5 January 2018

Volume: 7

Issue: 3

Electronic Location Identifier: e1408749

Affiliations

[a ]Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna , Bologna, Italy

[b ]Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Copenhagen University Hospital , Copenhagen, Denmark

[c ]ExpreS2ion Biotechnologies, SCION-DTU Science Park , Hørsholm, Denmark

[d ]Rizzoli Orthopedic Institute, Laboratory of Experimental Oncology , Bologna, Italy

[e ]Division of Surgical Oncology, Department of Surgery and Department of Microbiology, Immunology and Molecular Genetics, The Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California , Los Angeles, CA, USA

Author notes

CONTACT Professor Pier-Luigi Lollini, Ph.D. pierluigi.lollini@ 123456unibo.it Laboratory of Experimental Oncology , Bologna, Italy

CONTACT Adam F. Sander, asander@ 123456sund.ku.dk Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen , Nørre Allé 14, Maersktårnet, Building 07-11-85, 2200, Copenhagen N, Denmark

Supplemental data for this article can be accessed on the publisher's website.

[†]

A.P. and S.T. contributed equally to this work.

[‡]

P.N and A.F.S. contributed equally to this work.

Author information

Arianna Palladini https://orcid.org/0000-0001-6105-4895

Giordano Nicoletti https://orcid.org/0000-0001-7050-7833

Tania Balboni https://orcid.org/0000-0001-5716-4602

Thor G. Theander https://orcid.org/0000-0002-3509-7514

Morten A. Nielsen https://orcid.org/0000-0003-2668-4992

Ali Salanti https://orcid.org/0000-0003-2207-5575

Patrizia Nanni https://orcid.org/0000-0001-5319-0803

Article

Publisher ID: 1408749

DOI: 10.1080/2162402X.2017.1408749

PMC ID: 5790387

PubMed ID: 29399414

SO-VID: a325de83-a405-4474-a775-ff8257c53fbe

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

History

Date received : 28 September 2017

Date revision received : 16 November 2017

Date accepted : 17 November 2017

Page count

Figures: 6, Tables: 0, Equations: 0, References: 64, Pages: 12

Funding

Funded by: This work was supported by a grant to P-L Lollini (pier.lollini@unibo.it) from the Italian Association for Cancer Research (AIRC)

Award ID: IG15324

This work was supported by grants from the Danish Research Councils, The Eurostars program and the European Research councils (ERC). This work was also supported by a grant to P-L Lollini (pier.lollini@unibo.it) from the Italian Association for Cancer Research (AIRC), IG15324. The authors would like to thank Jens Hedelund Madsen for technical assistance.

Virus-like particle display of HER2 induces potent anti-cancer responses

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Malaria vaccine development

Most cited references 67

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns.

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