Regression of human pancreatic tumor xenografts in mice after a single systemic injection of recombinant vaccinia virus GLV-1h68.
Oncolytic virotherapy of tumors has shown promising results in both preclinical and clinical studies. Here, we investigated the therapeutic efficacy of a replication-competent vaccinia virus, GLV-1h68, against human pancreatic carcinomas in cell cultures and in nude mice. We found that GLV-1h68 was able to infect, replicate in, and lyse tumor cells in vitro. Virus-mediated marker gene expressions were readily detected. Moreover, s.c. PANC-1 pancreatic tumor xenografts were effectively treated by a single i.v. dose of GLV-1h68. Cancer killing was achieved with minimal toxicity. Viral titer analyses in homogenized organs and PANC-1 tumors showed that the mutant virus resides almost exclusively in the tumors and not in healthy organs. Except mild spleen enlargements, no histopathology changes were observed in any other organs 2 months after virus injection. Surprisingly, s.c. MIA PaCa-2 pancreatic tumors were treated with similar efficiency as PANC-1 tumors, although they differ significantly in sensitivity to viral lysis in cell cultures. When GLV-1h68 oncolytic viral therapy was used together with cisplatin or gemcitabine to treat PANC-1 tumors, the combination therapy resulted in enhanced and accelerated therapeutic results compared with the virus treatment alone. Profiling of proteins related to immune response revealed a significant proinflammatory immune response and marked activation of innate immunity in virus-colonized tumors. In conclusion, the GLV-1h68 strain showed outstanding therapeutic effects and a documented safety profile in mice, with great promise for future clinical development.
Yu
Yong A
YA
Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, CA 92109, USA.
Galanis
Charles
C
Woo
Yanghee
Y
Chen
Nanhai
N
Zhang
Qian
Q
Fong
Yuman
Y
Szalay
Aladar A
AA
D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015967:Gene Expression Regulation, Viral; D005819:Genetic Markers; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000821:virology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy* / Q000821:virology; D014615:Vaccinia / Q000276:immunology / Q000473:pathology / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D005819:Genetic Markers; D014764:Viral Proteins; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine