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CpG Therapy is Superior to BCG in an Orthotopic Bladder Cancer Model and Generates CD4+ T-cell Immunity
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 Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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 Oncology, Radiology and Clinical Immunology, 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.
Keyword [en]
Urinary Bladder Cancer, CpG ODNs, BCG, Immunotherapy, UBC, animal models, CD4+ T cell immunity, TLR-9, MB49
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-13048DOI: 10.1097/CJI.0b013e3181587d29ISI: 000251942400005PubMedID: 18157010OAI: oai:DiVA.org:uu-13048DiVA: diva2:40818
Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Immunological Checkpoint Blockade and TLR Stimulation for Improved Cancer Therapy
Open this publication in new window or tab >>Immunological Checkpoint Blockade and TLR Stimulation for Improved Cancer Therapy
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
TLR-stimulering och CTLA-4 samt PD-1 blockad för förbättrad cancerterapi
Abstract [en]

This thesis concerns the investigation of novel immunotherapies for cancer eradication. CpG therapy was used in order to target antigen-presenting cells (APCs), facilitating antigen presentation and activation of T cells. Blockade of the two major immune checkpoint regulators (CTLA-4 and PD-1) was also studied to ensure proper and sustained T cell activation. The therapies were investigated alone and compared to BCG, the standard immunotherapy in the clinic today for bladder cancer. In addition, CpG as well as BCG was combined with CTLA-4 or PD-1 blockade to examine if the combination could improve therapy.

Single and combination strategies were assessed in an experimental bladder cancer model. In addition, one of the therapies (local aCTLA-4 administration) was evaluated in an experimental pancreatic cancer model. To be able to study the effects of CpG in humans, a human whole blood loop system has been used. This allowed us to dissect the potential interplay between CpG and complement.

CpG was found to be superior to the conventional therapy, BCG, in our experimental model and T cells were required in order for effective therapy to occur. Used as a monotherapy, CTLA-4 blockade but not PD-1 blockade, prolonged survival of mice. When CTLA-4 or PD-1 blockade was combined with CpG, survival was enhanced and elevated levels of activated T cells were found in treated mice. In addition, Treg levels were decreased in the tumor area compared to tumors in control treated mice. CTLA-4 blockade was also effective when administrated locally, in proximity to the tumor. Compared to systemic CTLA-4 blockade, local administration gave less adverse events and sustained therapeutic success.

When CpG was investigated in a human whole blood loop system it was found to tightly interact with complement proteins. This is an interesting finding which warrants further investigation into the role of TLRs in complement biology. Tumor therapy could be affected either negatively or positively by this interaction.

The results presented herein are a foundation for incorporating these combination therapies into the clinic, specifically for bladder cancer but in a broader perspective, also for other solid tumors such as pancreatic cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 95 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 506
Keyword
CpG ODNs, TLR-9, CTLA-4, PD-1, PD-L1, B7. H1, immunotherapy, checkpoint blockade, bladder cancer, cancer, complement, TLRs, Compstatin, properdin, C3, experimental animal model, whole blood loop system, combination therapies
National Category
Immunology in the medical area Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-110147 (URN)978-91-554-7675-5 (ISBN)
Public defence
2010-01-29, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2009-12-23 Created: 2009-11-05 Last updated: 2009-12-23Bibliographically approved

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Mangsbo, Sara MEssand, MagnusLoskog, AngelicaTötterman, Thomas H

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