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Potent antitumor effects of CD154 transduced tumor cells in experimental bladder cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2001 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 166, no 3, 1093-1097 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Current intravesical immunotherapy for bladder cancer with bacillus Calmette-Guerin instillations is standard treatment for patients with high risk superficial tumors but relapses are common. We evaluated the tumor vaccine concept in murine bladder cancer by comparing tumor cell transduction with genes coding for the immunostimulatory molecules CD154, interleukin (IL)-12 and CD80 to design a novel vaccination strategy.

MATERIALS AND METHODS: Adenoviral vectors were used to transduce murine bladder cancer MB-49 cells with genes coding for CD154, IL-12 and CD80. Parental or transduced MB-49 cells were injected subcutaneously into syngeneic mice. The effects of transgene expression on tumorigenicity and the generation of protective immunological memory against challenge with parental tumor were studied.

RESULTS: All 76 animals injected with parental MB-49 cells had tumors within 8 to 12 days. Tumor cell expression of CD154 combined with IL-12 completely inhibited tumor outgrowth with all 21 mice tumor-free and CD154 transduction alone was almost as effective with 33 of 35 tumor-free. IL-12 production by tumor cells delayed tumor outgrowth and 4 of 10 mice remained tumor-free. Over expression of CD80 had no effect on tumorigenicity. CD154 expressing tumors were rapidly infiltrated with large numbers of CD4+ and CD8+ T cells. Mice vaccinated 4 times with adenoviral CD154 transduced MB-49 cells were completely protected against challenge with parental tumor. Co-injection of CD154 modified cells with parental MB-49 cells retarded tumor growth.

CONCLUSIONS: Our experimental results suggest that the potent antitumor effects of CD154 gene transduction should be considered for immunostimulatory gene therapy for bladder cancer.

Place, publisher, year, edition, pages
2001. Vol. 166, no 3, 1093-1097 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89984DOI: 10.1016/S0022-5347(05)65928-9PubMedID: 11490305OAI: oai:DiVA.org:uu-89984DiVA: diva2:161975
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2010-09-13Bibliographically 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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Tötterman, Thomas H.
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