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Development of a therapeutic vaccine targeting blood vessels in primary tumors and metastases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Tumor vascular biology (Anna-Karin Olsson))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Tumor vascular biology (Anna-Karin Olsson))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Tumor vascular biology (Anna-Karin Olsson))
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Lars Hellman)
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2012 (English)Manuscript (preprint) (Other academic)
Place, publisher, year, edition, pages
2012.
Keyword [en]
ED-B, ED-A, C-domain of TNC, immunization, tumor, vascular, therapeutic, vaccination
National Category
Microbiology in the medical area Cell and Molecular Biology Immunology in the medical area
Research subject
Biomedical Laboratory Science
Identifiers
URN: urn:nbn:se:uu:diva-170429OAI: oai:DiVA.org:uu-170429DiVA: diva2:509686
Available from: 2012-03-13 Created: 2012-03-12 Last updated: 2012-08-01
In thesis
1. Development of a Cancer Vaccine Targeting Tumor Blood Vessels
Open this publication in new window or tab >>Development of a Cancer Vaccine Targeting Tumor Blood Vessels
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A treatment strategy for cancer is the suppression of tumor growth by directing an immune response to the tumor vessels, which will destroy the tissue.

In this thesis we describe the development of a vaccine that targets antigens expressed around angiogenic vasculature in most solid tumors. These antigens are alternative spliced extra domains of glycoproteins present in the extracellular matrix; e.g. the extra domain-B (ED-B) and extra domain-A (ED-A) of fibronectin and the C-domain of tenascin-C (TNCC).

We show that it is possible to break self-tolerance and induce a strong antibody response against ED-B by vaccination. Furthermore, tumor growth was inhibited and the changes observed in the tumor tissue were consistent with an attack of the tumor vasculature by the immune system.

For clinical development of therapeutic vaccines, targeting self-molecules like ED-B, a potent but non-toxic biodegradable adjuvant is required. The squalene-based Montanide ISA 720 (M720) in combination with CpG DNA fulfilled these requirements and induced an equally strong anti-self immune response as the preclinical golden standard Freund’s adjuvant. We have further characterized the immune response against ED-B generated with the adjuvant M720/GpG. 

The ED-B vaccine also inhibited tumor growth in a therapeutic setting in a transgenic mouse model of pancreatic insulinoma in which tumorigenesis was already initiated. Furthermore, antibodies against ED-A and TNCC could be induced in mice and rabbits. We analyzed the expression of ED-A in breast tumors of transgenic MMTV-PyMT mice, a metastatic breast cancer model, with the aim to use this model to study the effect of an ED-A vaccine on metastasis. We also detected ED-B in canine mammary tumor tissue. Therefore vascular antigens might also represent potential therapeutic targets in dogs. 

All together our preclinical data demonstrate that a vaccine targeting tumor blood vessels is a promising new approach for cancer treatment. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 755
Keyword
Vaccine, Therapeutic, Cancer, Tumor, Angiogenesis, Immunization, Vascular, Extracellular matrix
National Category
Cell and Molecular Biology Immunology in the medical area Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedical Laboratory Science; Medical Cell Biology; Oncology; Medical Science
Identifiers
urn:nbn:se:uu:diva-170887 (URN)978-91-554-8317-3 (ISBN)
Public defence
2012-05-11, B42, Biomedicinsk Centrum (BMC), Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2012-04-19 Created: 2012-03-13 Last updated: 2012-08-01Bibliographically approved

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Huijbers, Elisabeth JM

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