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

Adair, RA, Roulstone, V, Scott, KJ, Morgan, R, Nuovo, GJ, Fuller, M, Beirne, D, West, EJ, Jennings, VA, Rose, A, Kyula, J, Fraser, S, Dave, R, Anthoney, DA, Merrick, A, Prestwich, R, Aldouri, A, Donnelly, O, Pandha, H, Coffey, M, Selby, P, Vile, R, Toogood, G, Harrington, K and Melcher, AA (2012) Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Sci Transl Med, 4 (138).

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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.

Item Type: Article
Authors :
NameEmailORCID
Adair, RAUNSPECIFIEDUNSPECIFIED
Roulstone, VUNSPECIFIEDUNSPECIFIED
Scott, KJUNSPECIFIEDUNSPECIFIED
Morgan, RUNSPECIFIEDUNSPECIFIED
Nuovo, GJUNSPECIFIEDUNSPECIFIED
Fuller, MUNSPECIFIEDUNSPECIFIED
Beirne, DUNSPECIFIEDUNSPECIFIED
West, EJUNSPECIFIEDUNSPECIFIED
Jennings, VAUNSPECIFIEDUNSPECIFIED
Rose, AUNSPECIFIEDUNSPECIFIED
Kyula, JUNSPECIFIEDUNSPECIFIED
Fraser, SUNSPECIFIEDUNSPECIFIED
Dave, RUNSPECIFIEDUNSPECIFIED
Anthoney, DAUNSPECIFIEDUNSPECIFIED
Merrick, AUNSPECIFIEDUNSPECIFIED
Prestwich, RUNSPECIFIEDUNSPECIFIED
Aldouri, AUNSPECIFIEDUNSPECIFIED
Donnelly, OUNSPECIFIEDUNSPECIFIED
Pandha, Hh.pandha@surrey.ac.ukUNSPECIFIED
Coffey, MUNSPECIFIEDUNSPECIFIED
Selby, PUNSPECIFIEDUNSPECIFIED
Vile, RUNSPECIFIEDUNSPECIFIED
Toogood, GUNSPECIFIEDUNSPECIFIED
Harrington, KUNSPECIFIEDUNSPECIFIED
Melcher, AAUNSPECIFIEDUNSPECIFIED
Date : 13 June 2012
Identification Number : https://doi.org/10.1126/scitranslmed.3003578
Uncontrolled Keywords : Aged, Antibodies, Neutralizing, Blood Platelets, Colorectal Neoplasms, Female, Genome, Viral, Granulocytes, Humans, Liver Neoplasms, Male, Middle Aged, Oncolytic Virotherapy, Oncolytic Viruses, Virus Replication
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:44
Last Modified : 17 May 2017 14:44
URI: http://epubs.surrey.ac.uk/id/eprint/824889

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