Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus.
Previously, we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-Aequorea green fluorescent protein fusion, beta-galactosidase, and beta-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase) and A56R (encoding hemagglutinin) loci of the viral genome, respectively. I.v. injections of GLV-1h68 (1x10(7) plaque-forming unit per mouse) into nude mice with established (approximately 300-500 mm3) s.c. GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity, and oncolytic efficacy. GLV-1h68 showed an enhanced tumor targeting specificity and much reduced toxicity compared with its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of IFN-stimulated genes (STAT-1 and IRF-7), cytokines, chemokines, and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers.
Zhang
Qian
Q
Genelux Corporation, San Diego Science Center, San Diego, California 92109, USA.
Yu
Yong A
YA
Wang
Ena
E
Chen
Nanhai
N
Danner
Robert L
RL
Munson
Peter J
PJ
Marincola
Francesco M
FM
Szalay
Aladar A
AA
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D002522:Chlorocebus aethiops; D005260:Female; D005347:Fibroblasts; D005966:Glucuronidase / Q000096:biosynthesis / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D011993:Recombinant Fusion Proteins; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; D049410:Luciferases, Renilla; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D005966:Glucuronidase