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CpG oligonucleotide therapy cures subcutaneous and orthotopic tumors and evokes protective immunity in murine bladder cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2005 (English)In: Journal of immunotherapy (1997), ISSN 1524-9557, E-ISSN 1537-4513, Vol. 28, no 1, 20-27 p.Article in journal (Refereed) Published
Abstract [en]

Bacillus Calmette-Guerin (BCG) instillation is standard immunotherapy for superficial bladder carcinoma. However, many patients become refractory to BCG, giving impetus to the development of alternative therapies. CpG oligodeoxynucleotide (ODN) therapy has been shown to promote T(H)1-oriented antitumor responses in various tumor models. To investigate its therapeutic effect in bladder cancer, we used different CpG ODNs to treat C57BL/6 mice bearing the subcutaneous murine bladder tumor MB49. CpG type B ODN 1668 was superior at inhibiting tumor growth, leading to complete regression of large tumors. More importantly, CpG ODN 1668 also regressed orthotopically growing MB49 tumors for the first time. Rechallenge of CpG ODN-cured mice with MB49 showed that a majority of the mice were protected long term, demonstrating that CpG ODN therapy evokes a memory response. Adenoviral vectors (Ad) encoding CD40L, tumor necrosis factor-related activation-induced cytokine, lymphotactin, interleukin (IL) 2, and IL-15 were also investigated. AdCD40L and AdIL-15 transduction could abolish MB49 tumorigenicity, and these vectors were combined with CpG ODN 1668 to investigate any enhanced effects. No such effects were seen. All groups of mice treated with CpG ODNs, alone or in combination with adenoviral vector, exhibited increased serum concentrations of IL-12, indicative of a T(H)1 response. Our results show that CpG ODN therapy cures established subcutaneous and orthotopic bladder cancer via a T(H)1-mediated response and provides long-lasting protective immunity.

Place, publisher, year, edition, pages
2005. Vol. 28, no 1, 20-27 p.
Keyword [en]
Adenoviridae/genetics, Adjuvants; Immunologic/therapeutic use, Administration; Intravesical, Animals, CD40 Ligand/genetics/immunology, Carcinoma; Transitional Cell/immunology/pathology/*therapy, Cell Line, Cell Line; Tumor, Chemokines; C/genetics/immunology, DNA/therapeutic use, Dose-Response Relationship; Immunologic, Female, Gene Therapy, Genetic Vectors/genetics, Humans, Immunotherapy/*methods, Interleukin-12/blood, Interleukin-15/genetics/immunology, Mice, Mice; Inbred C57BL, Neoplasm Transplantation, Oligodeoxyribonucleotides/administration & dosage/*therapeutic use, Survival Rate, Transfection, Urinary Bladder Neoplasms/immunology/*prevention & control/therapy
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94283PubMedID: 15614041OAI: oai:DiVA.org:uu-94283DiVA: diva2:168082
Available from: 2006-04-11 Created: 2006-04-11 Last updated: 2010-09-15Bibliographically approved
In thesis
1. Cancer Immunotherapy: A Preclinical Study of Urinary Bladder Cancer
Open this publication in new window or tab >>Cancer Immunotherapy: A Preclinical Study of Urinary Bladder Cancer
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacillus Calmette Guérin (BCG), or attenuated Mycobacterium bovis, is the gold standard of immunotherapy in the clinic to treat superficial bladder cancer. However, setbacks remain due to a high recurrence rate, side effects, and BCG-refractory disease. In this thesis, we explored the use of novel immunotherapeutic agents such as CpG oligodeoxynucleotides (CpG ODNs) or synthetic ODNs containing unmethylated CpG dinucleotides. Since unmethylated CpG motifs are predominant in bacterial but not vertebrate DNA, they function as a “danger signal” leading to a potent immune response.

To be able to test various immunotherapeutic agents, we optimized subcutaneous (s.c.), metastatic, and orthotopic models using the murine bladder-49 (MB49) cancer cell line. In the orthotopic model, we show that poly-L-lysine promotes MB49 attachment to the bladder leading to 100% tumor take. In addition, Clorpactin (sodium oxychlorosene) potently enhances adenoviral transduction in the bladder.

Utilizing the MB49 model, we compare CpG ODNs with BCG and demonstrate the increased efficacy of CpG ODNs which could cure both s.c. and aggressive orthotopic bladder cancer. In our model, type B ODNs were most optimal and the antitumor response required T cells in order to induce regression and tumor-specific immunity. We also combined CpG ODNs with adenoviral vectors (Ad) expressing the immunostimulatory molecules CD40L, TRANCE, lymphotactin, IL2 or IL15. However, we show that CpG ODNs are effective as a monotherapy and adenoviral vectors did not enhance the effect.

AdCD40L was also used to genetically modify human dendritic cells (DCs). AdCD40L-transduced DCs not only had a higher and prolonged expression of the Th1 cytokine IL12 compared to TNFα-matured DCs, but CD40L-activated DCs could also resist the suppressive effects of IL10 and TGFβ. Since TNFα is commonly used in clinical DC vaccination protocols and because tumors often secrete immunosuppressive cytokines, these data have important implications for optimizing cancer immunotherapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 134
Medicine, immunotherapy, bladder carcinoma, cancer, CpG ODNs, Adenoviral vector, CD40L, TRANCE, Lymphotactin, IL2, IL15, Medicin
urn:nbn:se:uu:diva-6761 (URN)91-554-6525-0 (ISBN)
Public defence
2006-05-05, Rudbeck Hall, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2006-04-11 Created: 2006-04-11Bibliographically approved

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Ninalga, ChristinaLoskog, AngelicaEssand, MagnusTötterman, Thomas H.
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