Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients.
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.
Leeds Institute of Molecular Medicine, St. James's University Hospital, and Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS9 7TF, UK.
Robert A
RA
Adair
Victoria
V
Roulstone
Karen J
KJ
Scott
Ruth
R
Morgan
Gerard J
GJ
Nuovo
Martin
M
Fuller
Deborah
D
Beirne
Emma J
EJ
West
Victoria A
VA
Jennings
Ailsa
A
Rose
Joan
J
Kyula
Sheila
S
Fraser
Rajiv
R
Dave
David A
DA
Anthoney
Alison
A
Merrick
Robin
R
Prestwich
Amer
A
Aldouri
Oliver
O
Donnelly
Hardev
H
Pandha
Matt
M
Coffey
Peter
P
Selby
Richard
R
Vile
Giles
G
Toogood
Kevin
K
Harrington
Alan A
AA
Melcher
D000368:Aged; D057134:Antibodies, Neutralizing / Q000276:immunology; D001792:Blood Platelets / Q000821:virology; D015179:Colorectal Neoplasms / Q000601:surgery / Q000628:therapy; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D006098:Granulocytes / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000601:surgery / Q000628:therapy; D008297:Male; D008875:Middle Aged; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
D057134:Antibodies, Neutralizing