Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients

Robert A. Adair, Victoria Roulstone, Karen J. Scott, Ruth Morgan, Gerard J. Nuovo, Martin Fuller, Deborah Beirne, Emma J. West, Victoria A. Jennings, Ailsa Rose, Joan Kyula, Sheila Fraser, Rajiv Dave, David A. Anthoney, Alison Merrick, Robin Prestwich, Amer Aldouri, Oliver Donnelly, Hardev Pandha, Matt CoffeyPeter Selby, Richard Vile, Giles Toogood, Kevin Harrington, Alan A. Melcher

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo.

Original languageEnglish (US)
Article number138ra77
JournalScience translational medicine
Volume4
Issue number138
DOIs
StatePublished - Jun 13 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Adair, R. A., Roulstone, V., Scott, K. J., Morgan, R., Nuovo, G. J., Fuller, M., Beirne, D., West, E. J., Jennings, V. A., Rose, A., Kyula, J., Fraser, S., Dave, R., Anthoney, D. A., Merrick, A., Prestwich, R., Aldouri, A., Donnelly, O., Pandha, H., ... Melcher, A. A. (2012). Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Science translational medicine, 4(138), [138ra77]. https://doi.org/10.1126/scitranslmed.3003578