Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy.

Publication Type:

Journal Article

Source:

Molecular therapy : the journal of the American Society of Gene Therapy, Volume 19, Issue 10, p.1802-12 (2011)

Keywords:

Antineoplastic Agentsdigestive disease, digestive deseases Combined Modality Therapydigestive disease, digestive deseases Drug Administration Scheduledigestive disease, digestive deseases Humansdigestive disease, digestive deseases Killer Cells, Naturaldigestive disease, digestive deseases Lymphocyte Activationdigestive disease, digestive deseases Neoplasmsdigestive disease, digestive deseases Oncolytic Virotherapydigestive disease, digestive deseases Paclitaxeldigestive disease, digestive deseases Reoviridaedigestive disease, digestive deseases Vascular Endothelial Growth Factor Adigestive disease, digestive deseases Virus Replication

Abstract:

We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses.