VEGF Blockade Decreases Tumor Uptake of Systemic Oncolytic Herpes Virus but Enhances Therapeutic Efficacy When Given After Virotherapy

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. Because systemic delivery of small molecule chemotherapy is enhanced by prior treatment with anti-angiogenic agents due to changes in intravascular-to-tumor interstitial pressure, we sought to determine if anti-angiogenic pretreatment increases antitumor efficacy of systemic virotherapy by increasing virus uptake into tumor. Virus biodistribution and anti-tumor effects were monitored in tumor-bearing mice given anti-human VEGF or anti-mouse VEGFR2 before or after an intravenous injection of virus. Without pretreatment, the average virus titers in the tumor samples amplified 1700-fold over 48 hours but were undetectable in other organs. Following anti-angiogenic treatment, average virus titers in the tumor samples were unchanged or in some cases decreased by up to 100-fold. Thus, anti-angiogenic pretreatment failed to improve tumor uptake of systemic oncolytic HSV, in contrast to previously reported enhanced uptake of small molecules. Superior tumor control due to the combined effects of virus and anti-VEGF was seen most dramatically when anti-VEGF was given after virus. Our data suggest intravenous oncolytic HSV can treat distant sites of disease and be enhanced by anti-angiogenic therapy, but only when given in the proper sequence.