Intravenous and isolated limb perfusion delivery of wild type and a tumor-selective replicating mutant vaccinia virus in nonhuman primates.
In this study we examine the safety, feasibility, and biodistribution of a tumor-selective mutant vaccinia (vvDD) and wild-type WR (vF13) vaccinia after delivery via intradermal or intravenous infection or isolated limb perfusion (ILP) in rhesus macaques. By intradermal inoculation, 10(6) PFU of vvDD caused a minimal skin reaction whereas vF13 caused marked erythema and necrosis with a peak indurated area of 108 cm2. By intravenous delivery, vvDD caused no clinical symptoms of viremia and no viral recovery from tissues, serum, saliva, urine, or feces. In contrast, vF13 caused symptoms of lethargy, anorexia, fever, and signs of viremia. Delivery of vF13 via ILP resulted in numerous cutaneous pox lesions localized solely to the perfused limb with high viral recovery in the perfused skin and muscle. ILP with vvDD resulted in no visible pox lesions and no clinical signs or symptoms of viremia. No long-term toxicity was identified after ILP with 10(9) PFU of vvDD, and no virus was recovered from any tissue, serum, saliva, urine, or fecal sample. These results suggest that vvDD appears to be safe in primates, and thus vvDD should be further investigated for clinical trial in human cancer patients.
Naik
Arpana M
AM
Center for Cancer Research, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Chalikonda
Sricharan
S
McCart
J Andrea
JA
Xu
Hui
H
Guo
Z Sheng
ZS
Langham
Gregory
G
Gardner
Donald
D
Mocellin
Simone
S
Lokshin
Anna E
AE
Moss
Bernard
B
Alexander
H Richard
HR
Bartlett
David L
DL
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D005121:Extremities / Q000821:virology; D005260:Female; D015316:Genetic Therapy / Q000379:methods* / Q000592:standards; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000592:standards*; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D007271:Injections, Intradermal; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000628:therapy*; D010455:Peptides / Q000235:genetics; D010477:Perfusion / Q000379:methods; D013937:Thymidine Kinase / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D000914:Antibodies, Viral; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D010455:Peptides; C051087:vaccinia growth factor; D013937:Thymidine Kinase