title: TOA02, a recombinant adenovirus with tumor-specific granulocyte macrophage colony-stimulating factor expression, has limited biodistribution and low toxicity in rhesus monkeys.
abstract: TOA02 is a genetically modified oncolytic adenovirus that contains human granulocyte macrophage colony-stimulating factor (hGM-CSF). It has been verified in vitro that TOA02 can specifically replicate in tumor cells that possess high telomerase reverse transcriptase activity and Rb pathway deficiency. However, the replication specificity, hGM-CSF expression, and toxicity of TOA02 in vivo are still unknown. Therefore, the biosafety of TOA02 remains a critical issue before its potential clinical use. In this study, viral replication and hGM-CSF expression levels were investigated in both xenograft nude mouse models and rhesus monkeys, and chronic toxicity was evaluated in rhesus monkeys. Our results show that (1) the replication and hGM-CSF expression of TOA02 are high in tumor model, (2) there are no hGM-CSF expression and continuous viral replication in rhesus monkeys except in pancreas and epididymis, and (3) the antiadenovirus antibody was positive in the chronic toxicity experiment, but pathological change of blood cytology and blood biochemistry were not found. There were no other histopathology lesions apart from skin inflammation of the administration region, lymphadenitis of draining lymph nodes. Our findings suggest that TOA02 is relatively safe for in vivo application, thus laying the foundation for future clinical trials with TOA02.
authors.affiliation: 1 School of Medical Laboratory Science, Chengdu Medical College , Chengdu 610500, PR China .
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Juecun
authors.initials: J
authors.lastname: Zheng
authors.forename: Qianchuan
authors.initials: Q
authors.lastname: He
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yu
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Hu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Deng
authors.forename: Shuching
authors.initials: S
authors.lastname: Chang
authors.forename: Fubing
authors.initials: F
authors.lastname: Shen
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000235:genetics*; D014018:Tissue Distribution; D036401:Toxicity Tests, Chronic; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor