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Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

Gene Therapy volume 10, pages 1982–1991 (2003)Cite this article

Abstract

Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Δ24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.

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Acknowledgements

We thank Dr G Giaccone for critically reading the manuscript. The research by VWB was made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences (KNAW) and JG was supported by the Federation Nationale des Centres de Lutte Contre le Cancer (FNLCC). This work was further supported by the Pasman Foundation and the Dutch Cancer Society (grant no. VU-2002-2594).

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Author notes

  1. T Würdinger

    Present address: Department of Infectious Diseases and Immunology, University of Utrecht, Utrecht, The Netherlands

Authors and Affiliations

  1. Division of Gene Therapy, Department of Medical Oncology, The Netherlands

    V W van Beusechem, D C J Mastenbroek, P B van den Doel, M L M Lamfers, J Grill, T Würdinger, H M Pinedo & W R Gerritsen

  2. Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands

    M L M Lamfers

  3. Department of Pediatric Oncology and UPRES-EA Pharmacology of New Drugs in Oncology, Institut Gustave Roussy, Villejuif, France

    J Grill

  4. Department of Therapeutic Gene Modulation, University Center for Pharmacy, Groningen, The Netherlands

    H J Haisma

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van Beusechem, V., Mastenbroek, D., van den Doel, P. et al. Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Gene Ther 10, 1982–1991 (2003). https://doi.org/10.1038/sj.gt.3302103

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