AdCD40L immunogene therapy for bladder carcinoma--the first phase I/IIa trial
2010 (English)In: Clin Cancer Res, Vol. 16, no 12, 3279-87 p.Article in journal (Refereed) Published
PURPOSE: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand 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 T(a) tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor 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 IFN-gamma increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells. CONCLUSIONS: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.
Place, publisher, year, edition, pages
2010. Vol. 16, no 12, 3279-87 p.
Adenoviridae/genetics, Aged, Aged, 80 and over, Benzenesulfonates/administration & dosage, CD40 Ligand/*genetics/immunology, Female, Gene Transfer Techniques, *Genetic Therapy, Genetic Vectors, Humans, Lymphocytes, Tumor-Infiltrating/immunology, Male, Middle Aged, Urinary Bladder Neoplasms/*therapy
IdentifiersURN: urn:nbn:se:umu:diva-110921ISBN: 1078-0432 (Print) 1078-0432 (Linking)OAI: oai:DiVA.org:umu-110921DiVA: diva2:865861
Malmstrom, Per-Uno Loskog, Angelica S I Lindqvist, Camilla A Mangsbo, Sara M Fransson, Moa Wanders, Alkwin Gardmark, Truls Totterman, Thomas H eng Clinical Trial, Phase I Clinical Trial, Phase II Research Support, Non-U.S. Gov't 2010/05/08 06:00 Clin Cancer Res. 2010 Jun 15;16(12):3279-87. doi: 10.1158/1078-0432.CCR-10-0385. Epub 2010 May 4.2015-10-292015-10-292015-10-29