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VEGF blockade decreases the tumor uptake of systemic oncolytic herpes virus but enhances therapeutic efficacy when given after virotherapy

Gene Therapy volume 17, pages 922–929 (2010)Cite this article

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Abstract

Effective therapies for metastatic sarcomas remain elusive. Oncolytic viruses have shown promise as anticancer agents, but their access to metastatic sites following systemic delivery is low. As systemic delivery of small-molecule chemotherapy is enhanced by previous treatment with antiangiogenic agents because of changes in intravascular-to-tumor interstitial pressure, we sought to determine whether antiangiogenic pretreatment increases the antitumor efficacy of systemic virotherapy by increasing virus uptake into tumor. Virus biodistribution and antitumor effects were monitored in tumor-bearing mice given antihuman vascular endothelial growth factor (VEGF) or antimouse VEGFR2 before or after an intravenous (i.v.) injection of virus. Without pretreatment, the average virus titers in the tumor samples amplified 1700-fold over 48 h but were undetectable in other organs. After antiangiogenic treatment, average virus titers in the tumor samples were unchanged or in some cases decreased up to 100-fold. Thus, antiangiogenic pretreatment failed to improve the tumor uptake of systemic oncolytic herpes simplex virus (oHSV), in contrast to previously reported enhanced uptake of small molecules. Superior tumor control because of the combined effects of virus and anti-VEGF was seen most dramatically when anti-VEGF was given after virus. Our data suggest that i.v. oHSV can treat distant sites of disease and can be enhanced by antiangiogenic therapy, but only when given in the proper sequence.

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Acknowledgements

We thank Daniel Demopoulos, Cindy Lambert, Steve Mayer and Cindy Klotz (Hematology/Oncology Pharmacy at Cincinnati Children's Hospital Medical Center) for providing bevacizumab, Dan Hinklin (ImClone Systems) for DC101, E Antonio Chiocca (Ohio State University) for providing rRp450, David Krisky and Bill Goins (University of Pittsburgh) for production and purification of rRp450, and Arturo Maldonado for help with biostatistical analyses. This work was supported by Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, teeoffagainstcancer.org, the Katie Linz Foundation, The Limb Preservation Foundation, an American Cancer Society Fellowship Award (FKE) and NIH grant R01-CA114004 (TPC).

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  1. Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    F K Eshun, M A Currier, R A Gillespie, J L Fitzpatrick, W H Baird & T P Cripe

  2. Physician Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    W H Baird

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Eshun, F., Currier, M., Gillespie, R. et al. VEGF blockade decreases the tumor uptake of systemic oncolytic herpes virus but enhances therapeutic efficacy when given after virotherapy. Gene Ther 17, 922–929 (2010). https://doi.org/10.1038/gt.2010.82

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