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Development of a Cancer Vaccine Targeting Tumor Blood Vessels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Tumor vascular biology (Anna-Karin Olsson))
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 [en]
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: urn:nbn:se:uu:diva-170887ISBN: 978-91-554-8317-3 (print)OAI: oai:DiVA.org:uu-170887DiVA: diva2:512413
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
List of papers
1. Vaccination against the extra domain-B of fibronectin as a novel tumor therapy
Open this publication in new window or tab >>Vaccination against the extra domain-B of fibronectin as a novel tumor therapy
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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.

Keyword
therapeutic, immunization, neovascularization, extracellular matrix, angiogenesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135097 (URN)10.1096/fj.10-163022 (DOI)000283861100038 ()
Available from: 2010-12-06 Created: 2010-12-03 Last updated: 2017-12-11Bibliographically approved
2. Identification of potent biodegradable adjuvants that efficiently break self-tolerance: a key issue in the development of therapeutic vaccines
Open this publication in new window or tab >>Identification of potent biodegradable adjuvants that efficiently break self-tolerance: a key issue in the development of therapeutic vaccines
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2009 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 1, 48-52 p.Article in journal (Refereed) Published
Abstract [en]

Monoclonal antibodies are used successfully in the treatment of many human disorders. However, these antibodies are expensive and have in many countries put a major strain on the health care economy. Therapeutic vaccines, directed against the same target molecules, may offer a solution to this problem. Vaccines usually involve lower amount of recombinant protein, approximately 10,000-20,000 times less, which is significantly more cost effective. Attempts to develop such therapeutic vaccines have also been made. However, their efficacy has been limited by the lack of potent immunostimulatory compounds, adjuvants, for human use. To address this problem we have conducted a broad screening for adjuvants that can enhance the efficacy of therapeutic vaccines, whilst at the same time being non-toxic and biodegradable. We have now identified adjuvants that show these desired characteristics. A combination of Montanide ISA720 and phosphorothioate stabilized CpG stimulatory DNA, induced similar or even higher anti-self-antibody titers compared to Freund's adjuvant, currently the most potent, but also toxic, adjuvant available. This finding removes one of the major limiting factors in the field and facilitates the development of a broad range of novel therapeutic vaccines.

Keyword
Adjuvant, Anti-self-response, CpG, Stimulatory DNA, Therapeutic vaccines
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-119720 (URN)10.1016/j.vaccine.2009.09.122 (DOI)000274869200007 ()19835827 (PubMedID)
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
3. The non-toxic and biodegradable adjuvant Montanide ISA 720/CpG can replace Freund's in a cancer vaccine targeting ED-B-a prerequisite for clinical development
Open this publication in new window or tab >>The non-toxic and biodegradable adjuvant Montanide ISA 720/CpG can replace Freund's in a cancer vaccine targeting ED-B-a prerequisite for clinical development
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2012 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 2, 225-230 p.Article in journal (Refereed) Published
Abstract [en]

We have recently shown that immunization against the extra domain-B (ED-B) of fibronectin, using Freund's adjuvant, reduces tumor growth in mice by 70%. In the present study we compare the immune response generated against ED-B using the non-toxic and biodegradable adjuvant Montanide ISA 720/CpG with the response elicited by Freund's adjuvant. Montanide ISA 720/CpG induced anti-ED-B antibodies with higher avidity and less variable levels between individuals than Freund's. Moreover, the duration of the immune response was longer and the generation of anti-ED-B antibodies in naïve mice was faster, when Montanide ISA 720/CpG was used. We conclude that it is possible to replace the mineral oil based adjuvant Freund's with an adjuvant acceptable for human use, which is a prerequisite for transfer of the ED-B vaccine to the clinic.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-162893 (URN)10.1016/j.vaccine.2011.11.010 (DOI)000299971800019 ()22079080 (PubMedID)
Available from: 2011-12-06 Created: 2011-12-06 Last updated: 2017-12-08Bibliographically approved
4. Development of a therapeutic vaccine targeting blood vessels in primary tumors and metastases
Open this publication in new window or tab >>Development of a therapeutic vaccine targeting blood vessels in primary tumors and metastases
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2012 (English)Manuscript (preprint) (Other academic)
Keyword
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:nbn:se:uu:diva-170429 (URN)
Available from: 2012-03-13 Created: 2012-03-12 Last updated: 2012-08-01

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