uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Vaccination against the extra domain-B of fibronectin as a novel tumor therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Show others and affiliations
2010 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, ISSN 20634349, Vol. 24, no 11, 4535-4544 p.Article in journal (Refereed) Published
Abstract [en]

Monoclonal antibody-based therapies have made an important contribution to current treatment strategies for cancer and autoimmune disease. However, the cost for these new drugs puts a significant strain on the health-care economy, resulting in limited availability for patients. Therapeutic vaccination, defined as induction of immunity against a disease-related self-molecule, is therefore an attractive alternative. To analyze the potential of such an approach, we have developed a vaccine against the extra domain-B (ED-B) of fibronectin. This 91-aa domain, inserted by alternative splicing, is expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, ED-B is highly expressed around angiogenic vasculature, such as in tumorigenesis. Here, we demonstrate that it is possible to break self-tolerance and induce a strong antibody response against ED-B by vaccination. Nineteen of 20 vaccinated mice responded with production of anti-ED-B antibodies and displayed a 70% reduction in tumor size compared to those lacking anti-ED-B antibodies. Analysis of the tumor tissue revealed that immunization against ED-B induced several changes, consistent with an attack by the immune system. These data show that tumor vascular antigens are highly interesting candidates for development of therapeutic vaccines targeting solid tumors.

Place, publisher, year, edition, pages
2010. Vol. 24, no 11, 4535-4544 p.
Keyword [en]
therapeutic, immunization, neovascularization, extracellular matrix, angiogenesis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-135097DOI: 10.1096/fj.10-163022ISI: 000283861100038OAI: oai:DiVA.org:uu-135097DiVA: diva2:374708
Available from: 2010-12-06 Created: 2010-12-03 Last updated: 2017-12-11Bibliographically approved
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
2. Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis
Open this publication in new window or tab >>Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Induction of an endogenous antibody response by therapeutic vaccination could provide an alternative to cost-intensive monoclonal antibody-based treatments for cancer. Since the target of a cancer vaccine will most likely be a self-antigen, self-tolerance of the immune system must be circumvented. Using fusion proteins consisting of the self-antigen to be targeted and a part derived from a foreign antigen, it is possible to break tolerance against the self-antigen. Furthermore, a potent adjuvant is required to support an immune response against a self-molecule. Currently no adjuvant suitable for this purpose is approved for use in humans.

This thesis describes the development of a therapeutic vaccine targeting the vasculature of tumors. As tumor cells have developed strategies to escape immune surveillance, targeting of molecules associated with the tumor stroma is an interesting alternative. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin and the glycan-binding protein galectin-1 are selectively expressed during events of tumor angiogenesis. We have designed recombinant proteins to target ED-B, ED-A and galectin-1, containing bacterial thioredoxin (TRX) as a non-self part, resulting in TRX-EDB, TRX-EDA and TRX-Gal-1. Vaccination against ED-B induced anti-ED-B antibodies and inhibited growth of subcutaneous fibrosarcoma. Immunization against ED-A decreased tumor burden and reduced the number of lung metastases in the MMTV-PyMT model for metastatic mammary carcinoma in a therapeutic setting. Analysis of the tumor tissue from ED-B and ED-A-immunized mice indicated an attack of the tumor vasculature by the immune system. Finally, we show that galectin-1 immunization reduced tumor burden and increased leukocyte numbers in the tumor tissue. Galectin-1 is pro-angiogenic and immunosuppressive, and therefore allows simultaneous targeting of fundamental characteristics of tumorigenesis. We furthermore show that the biodegradable squalene-based Montanide ISA 720 combined with CpG oligo 1826 (M720/CpG) is at least as potent as Freund’s adjuvant with respect to breaking self-tolerance, when comparing several immunological parameters. Freund’s is a potent but toxic adjuvant used in the majority of preclinical studies.

The work presented in this thesis shows that therapeutic cancer vaccines targeting the tumor vasculature are a feasible and promising approach for cancer therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1017
Keyword
tumor, therapeutic, cancer vaccine, angiogenesis, vasculature, fibronectin, galectin-1
National Category
Cancer and Oncology Immunology in the medical area Cell and Molecular Biology
Research subject
Medical Cell Biology; Oncology; Biomedical Laboratory Science; Medical Science
Identifiers
urn:nbn:se:uu:diva-229572 (URN)978-91-554-8998-4 (ISBN)
Public defence
2014-09-26, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-09-03 Created: 2014-08-11 Last updated: 2014-09-08

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Ringvall, MariaFemel, JuliaOlsson, Anna-Karin

Search in DiVA

By author/editor
Ringvall, MariaFemel, JuliaOlsson, Anna-Karin
By organisation
Department of Medical Biochemistry and MicrobiologyDepartment of Genetics and PathologyDepartment of Cell and Molecular Biology
In the same journal
The FASEB Journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 732 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf