Effective Gene-Viral Therapy for Telomerase-Positive Cancers by Selective Replicative-Competent Adenovirus Combining with Endostatin Gene
Qi ZhangMingming NieJonathan S. T. ShamChangqing SuHuibin XueDaniel ChuaWeiguo WangZhenfu CuiYongjing LiuChen LiuMinghong JiangGuoen FangXinyuan LiuMengchao WuQijun Qian
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Abstract Gene-viral therapy, which uses replication-selective transgene-expressing viruses to manage tumors, can exploit the virtues of gene therapy and virotherapy and overcome the limitations of conventional gene therapy. Using a human telomerase reverse transcriptase-targeted replicative adenovirus as an antiangiogenic gene transfer vector to target new angiogenesis and making use of its unrestrained proliferation are completely new concepts in tumor management. CNHK300-mE is a selective replication transgene-expressing adenovirus constructed to carry mouse endostatin gene therapeutically. Infection with CNHK300-mE was associated with selective replication of the adenovirus and production of mouse endostatin in telomerase-positive cancer cells. Endostatin secreted from a human gastric cell line, SGC-7901, infected with CNHK300-mE was significantly higher than that infected with nonreplicative adenovirus Ad-mE in vitro (800 ± 94.7 ng/ml versus 132.9 ± 9.9 ng/ml) and in vivo (610 ± 42 ng/ml versus 126 ± 13 ng/ml). Embryonic chorioallantoic membrane assay showed that the mouse endostatin secreted by CNHK300-mE inhibited angiogenesis efficiently and also induced distortion of pre-existing vasculature. CNHK300-mE exhibited a superior suppression of xenografts in nude mice compared with CNHK300 and Ad-mE. In summary, we provided a more efficient gene-viral therapy strategy by combining oncolysis with antiangiogenesis.Keywords:
Endostatin
Angiostatin
Oncolytic adenovirus
Virotherapy
Oncolytic virotherapy is a promising and novel mean for treatment of solid tumors. A major challenge in virotherapy is tight restriction of viral replication to malignant cells combined with a large spectrum of potential target tumors.
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Abstract Gene-viral therapy, which uses replication-selective transgene-expressing viruses to manage tumors, can exploit the virtues of gene therapy and virotherapy and overcome the limitations of conventional gene therapy. Using a human telomerase reverse transcriptase-targeted replicative adenovirus as an antiangiogenic gene transfer vector to target new angiogenesis and making use of its unrestrained proliferation are completely new concepts in tumor management. CNHK300-mE is a selective replication transgene-expressing adenovirus constructed to carry mouse endostatin gene therapeutically. Infection with CNHK300-mE was associated with selective replication of the adenovirus and production of mouse endostatin in telomerase-positive cancer cells. Endostatin secreted from a human gastric cell line, SGC-7901, infected with CNHK300-mE was significantly higher than that infected with nonreplicative adenovirus Ad-mE in vitro (800 ± 94.7 ng/ml versus 132.9 ± 9.9 ng/ml) and in vivo (610 ± 42 ng/ml versus 126 ± 13 ng/ml). Embryonic chorioallantoic membrane assay showed that the mouse endostatin secreted by CNHK300-mE inhibited angiogenesis efficiently and also induced distortion of pre-existing vasculature. CNHK300-mE exhibited a superior suppression of xenografts in nude mice compared with CNHK300 and Ad-mE. In summary, we provided a more efficient gene-viral therapy strategy by combining oncolysis with antiangiogenesis.
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Virotherapy with oncolytic viruses is based on the use of tumor specific replicating virus. The oncolytic viruses have capacity for destruction of tumors and produce new infectious virus particles that will infect surrounding tumor cells and spread throughout the tumor. They have been used as potential vectors to express therapeutic genes in tumor cells. In order to allow transgene expression in the controlled and predicted manner, we generated oncolytic adenoviral vectors with transgene driven by major late promoter (MLP). The reporter gene HcRed and therapeutic genes Mda7/IL-24 and TRAIL have been incorporated into this vector. Our data showed that transgene expression was not detectable in the first hours after infection. The high level of transgene expression was found at 24 and 48 hours after infection. The expression level of transgenes was dramatic higher in tumor cells than normal cells infected with our vectors. Our results supported that high level of transgene expression in tumor cells was due to the viral replication. The vector carrying therapeutic genes have strong cytotoxicity to tumor cells. Our data indicated that oncolytic adenovirus could serve as potent vectors for delivery of therapeutic gene into tumor cells.
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Cancer gene therapy and oncolytic virotherapy have been studied extensively. However, their clinical application is hampered by their weak anticancer activity. We previously constructed a replicating adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of the adenoviral E1 genes, and causes selective lysis of human cancer cells. We hypothesized that combination adenoviral therapy containing OBP-301 and a nonreplicating adenovirus expressing the proapoptotic Bax gene could overcome the weakness and augment the anticancer efficacy of each modality. Combination treatment resulted in marked Bax protein expression and enhanced efficacy in in vitro cell viability assay, when compared with either single treatment. However, combination treatment was not as effective in suppressing both subcutaneous and pleural disseminated tumors compared with OBP-301 treatment alone. Further investigation revealed that combination treatment resulted in suppressed E1A protein expression associated with reduced viral replication. Our results suggest that Bax gene therapy in combination with oncolytic adenovirotherapy potentially augments their antitumor activity, but further improvements may be required to maximize the combinatorial effect in vivo, for the Bax gene expression to avoid interference with production of the oncolytic virus.
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Abstract Purpose: Recent studies showed that oncolytic adenoviruses not only have capacity for destruction of tumors but also can be used as potential vectors to express therapeutic genes for therapy of cancer. However, better specificity and mode of transgene expression are required to improve the efficacy and safety if this vector is applied for clinical application. Experimental Design: In this study, we have created adenoviral replication-based transgene expression system by replacement of 6.7K/gp19K of E3 genes with EGFP and IL-24 genes so that expression of transgenes should be controlled by adenoviral E3 promoter. Transgene expression, viral replication capacity, and cytotoxicity have been studied in tumor and normal cells. Antitumor efficacy was evaluated in animal model with established tumor. Results: Our data showed that expression of IL-24 could be detected at 6 h and reached the maximal level at 48 h after infection in tumor cells. The expression level was 14 times higher than that induced by cytomegalovirus promoter. Low level of IL-24 could be detected in normal cells only until 72 h after infection. The substitution of 6.7K/gp19K of E3 genes with transgenes did not affect viral replication in tumor cells. Strong cytotoxicity was observed only in tumor cells after infection with AdCN205-IL-24. Treatment of the established tumors induced high level of local expression of IL-24 in tumor cells and resulted in tumor regression. Conclusions: Our data showed that AdCN205-IL-24 can provide potent and safe vector for the therapy of cancer.
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Abstract Replication‐selective tumor‐specific viruses represent a novel approach for treating neoplastic diseases. These vectors are designed to induce virus‐mediated lysis of tumor cells after selective intracellular virus propagation. For targeting cancer cells, the use of tissue‐ or cell‐specific promoters that are expressed in diverse tumor types but silent in normal cells is required. Human telomerase is highly active in more than 85% of primary cancers, regardless of tissue origin, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (telomelysin, OBP ‐301) in which the hTERT promoter element drives expression of E1 genes. As only tumor cells that express the telomerase can activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Upon US Food and Drug Administration approval, a phase 1 dose‐escalation study of intratumoral injection of telomelysin for various solid tumors has been completed to confirm the safety, tolerability, and feasibility of the agent. Moreover, we found that adenoviral E1B 55‐ kD a protein in telomelysin inhibits the radiation‐induced DNA repair machinery. Thus, tumor cells infected with telomelysin could be rendered sensitive to ionizing radiation. Recently, we assessed the safety and efficacy of intratumoral injection of telomelysin with radiotherapy in esophageal cancer patients not suited for standard treatments. This review highlights some very promising clinical advances in cancer therapeutic technologies using telomerase‐specific oncolytic virotherapy.
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