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Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients

Cancer Gene Therapy volume 14, pages 211–219 (2007)Cite this article

Abstract

Clinical trials in malignant glioma have demonstrated excellent safety of recombinant adenovirus type 5 (Ad5) but lack of convincing efficacy. The overall low expression levels of the Coxsackie and Adenovirus receptor and the presence of high anti-Ad5-neutralizing antibody (NAb) titers in the human population are considered detrimental for consistency of clinical results. To identify an adenoviral vector better suited to infect primary glioma cells, we tested a library of fiber-chimeric Ad5-based adenoviral vectors on 12 fresh human glioma cell suspensions. Significantly improved marker gene expression was obtained with several Ad5-chimeric vectors, predominantly vectors carrying fiber molecules derived from B-group viruses (Ad11, Ad16, Ad35 and Ad50). We next tested Ad35 sero prevalence in sera derived from 90 Dutch cancer patients including 30 glioma patients and investigated the transduction efficiency of this vector in glioma cell suspensions. Our results demonstrate that the sero prevalence and the titers of NAb against Ad35 are significantly lower than against Ad5. Also, recombinant Ad35 has significantly increased ability to transfer a gene to primary glioma cells compared to Ad5. We thus conclude that Ad35 represents an interesting candidate vector for gene therapy of malignant glioma.

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Authors and Affiliations

  1. Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands

    E Brouwer, B de Leeuw, M ter Horst, D Nanda & P Sillevis Smitt

  2. Crucell Holland BV, Leiden, The Netherlands

    M J Havenga, O Ophorst, L Gijsbers, G Gillissen & J Goudsmit

  3. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    R C Hoeben

  4. Department of Neurosurgery, Free University Medical Center, Amsterdam, The Netherlands

    C Dirven

  5. Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, The Netherlands

    C J Avezaat

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  1. E Brouwer
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Correspondence to P Sillevis Smitt.

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Brouwer, E., Havenga, M., Ophorst, O. et al. Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients. Cancer Gene Ther 14, 211–219 (2007). https://doi.org/10.1038/sj.cgt.7701010

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