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CD40L immunogene therapy of cancer counteracts IL10 induced anergy
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-89985OAI: oai:DiVA.org:uu-89985DiVA: diva2:161976
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Immunogene Therapy of Bladder Carcinoma: A Preclinical Study
Open this publication in new window or tab >>Immunogene Therapy of Bladder Carcinoma: A Preclinical Study
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis comprises studies on murine and human models of bladder carcinoma with the aim to develop novel immunogene therapies. On the basis of the results presented in this thesis, a clinical trial is underway.

The potential of activating the immune system to combat cancer has long intrigued immunologists. Research has now been intensified and clinically effective treatments are beginning to materialize. We evaluated the induction of anti-tumor responses by inserting immunomodulating genes into tumor cells with adenovectors. Human biopsies and cell lines were positive for adenovirus attachment receptors, and cell lines were easily transduced. CD40L modified cells efficiently induced maturation of dendritic cell (DC). Phenotypical changes of AdCD40L transduced cells, such as increased apoptotic rate, upregulated MHC-I, Fas and TNFR may further strengthen the anti-tumor response.

CD40L modified murine bladder cancer cells activated systemic immunity upon vaccination and in situ injections of AdCD40L inhibited tumor progression. Cytotoxic assays revealed the presence of cytotoxic T cells (CTLs) in vaccinated mice. Many tumors have developed ways to evade the immune system. Bladder carcinoma is associated with immune escape mechanisms like IL10 production. We demonstrated that immunosuppression by IL10 inhibited CTL function and that IL10 suppression may be reverted by AdCD40L therapy.

In conclusion, AdCD40L therapy induces systemic immunity and inhibits tumor progression in murine models. The immunological mechanisms involve maturation of nearby DCs and CTL induction. AdCD40L therapy is effective despite immune escape mechanisms, e.g. IL10 secretion. The thesis argues for using AdCD40L immunogene therapy as a treatment of bladder carcinoma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 52 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1180
Oncology, Immunotherapy, Gene therapy, Immunogene therapy, CD40L, Bladder carcinoma, Onkologi
National Category
Cancer and Oncology
Research subject
Clinical Immunology
urn:nbn:se:uu:diva-2637 (URN)91-554-5402-X (ISBN)
Public defence
2002-10-11, Rudbecksalen, Uppsala, 13:15
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2010-09-15Bibliographically approved

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