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AdCD40L Immunogene Therapy for Bladder Carcinoma: The First Phase I/IIa Trial
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
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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2010 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 12, 3279-3287 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Immunotherapy with bacillus Calmette-Guérin (BCG) instillation is recommended for high-risk non-muscle invasive bladder cancer. BCG is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40L (AdCD40L) has shown efficacy in tumor models. CD40L stimulates systemic immunity and may be effective in local and invasive human disease. EXPERIMENTAL DESIGN: Patients with invasive bladder cancer scheduled for cystectomy or patients with Ta tumors were enrolled in a Phase I/IIa trial. Patients were treated with three cycles of intra-bladder Clorpactin WCS-90 prewash followed by AdCD40L instillation one week apart. Safety, gene transfer, immune effects and anti-tumor responses were monitored. RESULTS: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies and bladders were heavily infiltrated with T-cells. The effector marker IFNg increased in biopsies while levels of circulating T regulatory cells were reduced. Histological evaluation indicated that AdCD40L therapy reduced the load of malignant cells. CONCLUSION: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first utilizing AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation and should be further evaluated as single or adjuvant therapy for urothelial malignancies.

Place, publisher, year, edition, pages
2010. Vol. 16, no 12, 3279-3287 p.
Keyword [en]
AdCD40L, bladder carcinoma
National Category
Urology and Nephrology Cell and Molecular Biology
Research subject
Urology; Pathology
Identifiers
URN: urn:nbn:se:uu:diva-125943DOI: 10.1158/1078-0432.CCR-10-0385ISI: 000278749400023PubMedID: 20448220OAI: oai:DiVA.org:uu-125943DiVA: diva2:321427
Available from: 2010-05-31 Created: 2010-05-31 Last updated: 2017-12-12Bibliographically approved

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Malmström, Per-UnoLoskog, Angelica S. I.Tötterman, Thomas H.

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