A human adenoviral vector with a chimeric fiber from canine adenovirus type 1 results in novel expanded tropism for cancer gene therapy

• Published in: Gene therapy Vol. 12; no. 23; pp. 1696 - 1706
• Main Authors: STOFF-KHALILI, M. A, RIVERA, A. A, PEREBOEVA, L, SEIGAL, G. P, DALL, P, CURIEL, D. T, GLASGOW, J. N, LE, L. P, STOFF, A, EVERTS, M, TSURUTA, Y, KAWAKAMI, Y, BAUERSCHMITZ, G. J, MATHIS, J. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-12-2005
• Subjects: Adenovirus; Adenoviruses; Adenoviruses, Canine - genetics; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Applied cell therapy and gene therapy; Binding, Competitive; Biological and medical sciences; Biotechnology; Brain tumors; Capsid Proteins - genetics; Caveolin-1; Cell Line, Tumor; Clinical trials; DNA, Viral; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Gene transfer; Genetic aspects; Genetic Engineering; Genetic Therapy - methods; Genetic vectors; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Glioma; Health aspects; Health. Pharmaceutical industry; Humans; Industrial applications and implications. Economical aspects; Liver - metabolism; Liver - virology; Medical sciences; Methods; Neoplasms - therapy; Ovarian cancer; Ovarian Neoplasms - therapy; Physiological aspects; Serotypes; Transduction, Genetic - methods; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tropism; Tumor cell lines; United States; Human; Tropism; Adenoviridae; transductional targeting; Targeting; Canine adenovirus; Malignant tumor; Virus; Canine adenovirus 1; fiber chimerism; Mastadenovirus; cancer; Chimerism; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302588

The development of novel therapeutic strategies is imperative for the treatment of advanced cancers like ovarian cancer and glioma, which are resistant to most traditional treatment modalities. In this regard, adenoviral (Ad) cancer gene therapy is a promising approach. However, the gene delivery efficiency of human serotype 5 recombinant adenoviruses (Ad5) in cancer gene therapy clinical trials to date has been limited, mainly due to the paucity of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human cancer cells. To circumvent CAR deficiency, Ad5 vectors have been retargeted by creating chimeric fibers possessing the knob domains of alternate human Ad serotypes. Recently, more radical modifications based on 'xenotype' knob switching with non-human adenovirus have been exploited. Herein, we present the characterization of a novel vector derived from a recombinant Ad5 vector containing the canine adenovirus serotype 1 (CAV-1) knob (Ad5Luc1-CK1), the tropism of which has not been previously described. We compared the function of this vector with our other chimeric viruses displaying the CAV-2 knob (Ad5Luc1-CK2) and Ad3 knob (Ad5/3Luc1). Our data demonstrate that the CAV-1 knob can alter Ad5 tropism through the use of a CAR-independent entry pathway distinct from that of both Ad5Luc1-CK2 and Ad5/3-Luc1. In fact, the gene transfer efficiency of this novel vector in ovarian cancer cell lines, and more importantly in patient ovarian cancer primary tissue slice samples, was superior relative to all other vectors applied in this study. Thus, CAV-1 knob xenotype gene transfer represents a viable means to achieve enhanced transduction of low-CAR tumors.