期刊
CANCER RESEARCH
卷 65, 期 23, 页码 10663-10668出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-2534
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- NCI NIH HHS [R01 CA102139] Funding Source: Medline
- NINDS NIH HHS [R01 NS032677] Funding Source: Medline
Conditionally replicating herpes simplex virus type I (HSV-1) vectors are promising therapeutic agents for cancer. Certain antitumor functions may be added to oncolytic activities of recombinant HSV-1 vectors by inserting transgenes into the viral genome. Because conventional homologous recombination techniques had required time-consuming processes to create armed oncolytic HSV-1 vectors, we established an innovative construction system using bacterial artificial chromosome and two recombinase systems (Cre/loxP and FLPe/FRT). Using G47 Delta, a safe and efficacious oncolytic HSV-1 with triple gene mutations, as the backbone, this system allowed a rapid generation of multiple vectors with desired transgenes inserted in the deleted ICP6 locus. Four oncolytic HSV-1 vectors, expressing murine interleukin 18 (mIL-18), soluble murine B7-1 [B7-1-immunoglobulin (B7-1-Ig)], both, or none, were created simultaneously within 3 months. In vitro, all newly created recombinant vectors exhibited virus yields and cytopathic effects similar to the parental G47 Delta. In two inummocompetent mouse tumor models, TRAMP-C2 prostate cancer and Neuro2a neuroblastoma, the vector expressing both mIL-18 and B7-1-Ig showed a significant enhancement of antitumor efficacy via T-cell-mediated immune responses. The results show that arming with multiple transgenes can improve the efficacy of oncolytic HSV-1 vectors. The use of our system may facilitate the development and testing of various armed oncolytic HSV-1 vectors. (Cancer Res 2005; 65(23): 10663-8).
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