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CpG oligonucleotides demonstrate increased therapeutic efficacy compared to BCG in an aggressive orthotopic bladder cancer model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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2008 (English)In: Journal of immunotherapy (1997), ISSN 1524-9557, E-ISSN 1537-4513, Vol. 31, no 1, 34-42 p.Article in journal (Refereed) Published
Abstract [en]

Bacillus Calmette Guérin (BCG) immunotherapy has been successful in extending tumor remission in bladder cancer, the fifth most common cancer in men. However, relapses are frequent and some patients develop resistance to BCG. CpGs were previously demonstrated to be effective in the murine MB49 model. In this paper, we modeled a more aggressive orthotopic bladder cancer than previously studied. Moreover, we compared standard BCG immunotherapy side-by-side with the Toll-like receptor-9 agonist CpG. MB49 tumor-bearing mice were treated with BCG or CpG and survival as well as tumor progression were observed over time. Urine, blood, and tumors were collected and analyzed. Mice were rechallenged and evaluated for tumor-specific immunity. In this study, CpGs induced a complete response of large aggressive orthotopic MB49 bladder tumors, resulting in tumor-specific systemic immunity. Further, data indicated that this potent antitumor effect required T cells. A comparison of CpGs and BCG in both a highly and less aggressive orthotopic tumor model, and in a subcutaneous tumor model, demonstrated that CpGs were superior to BCG. In the orthotopic model, BCG induced a local cytokine storm during treatment initiation whereas CpG affected a more refined cytokine pattern over time. Increased levels of cytokines in serum correlated with enhanced survival in the subcutaneous model. Further, immune cell depletion studies demonstrated that CpG-induced protective immunity was CD4+ T-cell dependent. Taken together, our data suggest that CpGs are superior to BCG for bladder cancer immunotherapy. Thus, this potent new drug may be an attractive therapeutic alternative and should be evaluated in bladder cancer patients.

Place, publisher, year, edition, pages
2008. Vol. 31, no 1, 34-42 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94284DOI: 10.1097/CJI.0b013e3181587d29PubMedID: 18157010OAI: oai:DiVA.org:uu-94284DiVA: diva2:168083
Available from: 2006-04-11 Created: 2006-04-11 Last updated: 2015-03-01Bibliographically 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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