title: Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy.
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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Kottke
authors.forename: John
authors.initials: J
authors.lastname: Chester
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ilett
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.forename: Rosa
authors.initials: R
authors.lastname: Diaz
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.forename: Jose
authors.initials: J
authors.lastname: Pulido
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D017239:Paclitaxel / Q000008:administration & dosage; D012087:Reoviridae / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D014779:Virus Replication
chemical_list: D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel