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Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Anna-Karin Olsson)
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 [en]
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: urn:nbn:se:uu:diva-229572ISBN: 978-91-554-8998-4 (print)OAI: oai:DiVA.org:uu-229572DiVA: diva2:737116
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
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: 2014-09-08Bibliographically approved
2. 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
3. Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.
Open this publication in new window or tab >>Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.
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2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, 12418-12427 p.Article in journal (Refereed) Published
Abstract [en]

Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

Keyword
ED-A, immunization, tumor vasculature, therapeutic, cancer vaccine
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-229544 (URN)000348037700049 ()25360764 (PubMedID)
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2017-12-05Bibliographically approved
4. Targeting galectin-1 by vaccination suppresses tumor growth and promotes leukocyte recruitment to the tumor tissue
Open this publication in new window or tab >>Targeting galectin-1 by vaccination suppresses tumor growth and promotes leukocyte recruitment to the tumor tissue
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(English)Manuscript (preprint) (Other academic)
Keyword
galectin-1, immunization, tumor angiogenesis, therapeutic, cancer vaccine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-229569 (URN)
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2014-09-08

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