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

Kottke, Timothy, Chester, John D., Ilett, Elizabeth, Thompson, Jill, Diaz, Rosa Maria, Coffey, Matt, Selby, Peter, Nuovo, Gerard, Pulida, Jose, Mukhopadhyay, Debabrata, Pandha, Hardev, Harrington, Kevin, Melcher, Alan and Vile, Richard 2011. Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy. Molecular Therapy 19 (10) , pp. 1802-1812. 10.1038/mt.2011.147

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Nature Publishing Group
Funders: Paul Family Gift, Richard Schulze Family Foundation, Mayo Foundation, Cancer Research UK, NIH Grants CA107082, CA132734, and CA130878.
Last Modified: 04 Jun 2017 05:37
URI: http://orca.cf.ac.uk/id/eprint/52503

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