TY - JOUR
T1 - Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy
AU - Kottke, Timothy
AU - Chester, John
AU - Ilett, Elizabeth
AU - Thompson, Jill
AU - Diaz, Rosa
AU - Coffey, Matt
AU - Selby, Peter
AU - Nuovo, Gerard
AU - Pulido, Jose
AU - Mukhopadhyay, Debabrata
AU - Pandha, Hardev
AU - Harrington, Kevin
AU - Melcher, Alan
AU - Vile, Richard
N1 - Funding Information:
We thank Toni Higgins for expert secretarial assistance. This work was supported by the Paul Family Gift, the Richard Schulze Family Foundation, the Mayo Foundation, Cancer Research UK and by NIH Grants CA107082, CA132734, and CA130878.
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
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U2 - 10.1038/mt.2011.147
DO - 10.1038/mt.2011.147
M3 - Article
C2 - 21792179
AN - SCOPUS:80053566728
SN - 1525-0016
VL - 19
SP - 1802
EP - 1812
JO - Molecular Therapy
JF - Molecular Therapy
IS - 10
ER -