E1B-Deleted Adenovirus (<i>dl</i>1520) Gene Therapy for Patients with Primary and Secondary Liver Tumors

Habib, Nagy; Sarraf, Catherine; Mitry, Ragai R.; Havlík, R; Nicholls, Joanna P.; Kelly, Michael D.; Vernon, Clare C.; Gueret-Wardle, David; R, el-Masry; Salama, H. S.; Ahmed, Rasha R.; Michail, Nagy; Edward, E. Walsh; Jensen, S. L.

doi:10.1089/10430340150218369

Cited by 106 publications

(62 citation statements)

References 17 publications

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“…Clinically, combination of 5-FU with oncolytic virus Addl1520 for liver cancer was well tolerated. 60 A controlled clinical trial in which recurrent head and neck cancer patients being treated with cisplatin and 5-FU were also treated with an oncolytic Ad demonstrated stasis in virally injected tumors, whereas all noninjected tumors treated with chemotherapy alone progressed. 11 In clinical trials, the response rate for tumors in patients treated with combinations improved compared to tumors in patients treated with chemotherapy alone.…”

Section: Discussionmentioning

confidence: 99%

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

et al. 2004

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A potentially promising treatment of metastatic cancer is the systemic delivery of oncolytic adenoviruses. This requires engineering viruses which selectively replicate in tumors. We have constructed such an oncolytic adenovirus, OAS403, in which two early region genes are under the control of tumor-selective promoters that play a role in two key pathways involved in tumorigenesis. The early region E1A is controlled by the promoter for the E2F-1 gene, a transcription factor that primarily upregulates genes for cell growth. The E4 region is under control of the promoter for human telomerase reverse transcriptase, a gene upregulated in most cancer cells. OAS403 was evaluated in vitro on a panel of human cells and found to elicit tumor-selective cell killing. Also, OAS403 was less toxic in human hepatocyte cultures, as well as in vivo when compared to an oncolytic virus that lacked selective E4 control. A single intravenous injection of 3 Â 10 12 vp/kg in a Hep3B xenograft mouse tumor model led to significant antitumor efficacy. Additionally, systemic administration in a pre-established LNCaP prostate tumor model resulted in over 80% complete tumor regressions at a tolerable dose. Vector genome copy number was measured in tumors and livers at various times following tail vein injection and showed a selective time-dependent increase in tumors but not livers over 29 days. Furthermore, efficacy was significantly improved when OAS403 treatment was combined with doxorubicin. This virus holds promise for the treatment of a broad range of human cancers including metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

et al. 2004

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“…Many obstacles in vivo exist to limit the utilities of oncolytic adenovirus to its full potential, which are clearly exemplified by clinical trials with oncolytic adenovirus. 2,[26][27][28][29] Arming oncolytic adenovirus with therapeutic gene proved to be an effective approach to enhance the antitumoral potency and provided best chance for tumor eradication in vivo. Our present study is the first report to arm the E1A mutant with a therapeutic transgene although the delivery of therapeutic transgenes has been Abbreviations: CR, complete tumor regression; PBS, phosphate-buffered saline.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus-mediated transfer of the antisense chk2 selectively inhibits tumor growth in vitro and in vivo

et al. 2006

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Screening and identifying molecules target to checkpoint pathways has fostered the development of checkpoint-based anticancer strategies. Among these targets, inhibition of chk2 may induce cell death for tumors whose growth depends on enhanced chk2 activity. However, improvement of the potency and specificity of such therapeutics remains a major challenge. To resolve this problem, we constructed M3, a novel recombinant adenovirus with a 27-bp deletion in E1A CR2 region by which to realize tumorspecific replication, and an 829-bp of antisense chk2 fragment inserted into the E3 coding region. In this design, M3 exploited the native adenovirus E3 promoters to express antisense chk2 cDNA in a viral replication-dependent fashion, and preferentially silenced the chk2 gene in tumor cells. In vitro and in vivo assays confirmed that downregulated chk2 expression induced by M3 infection was tumor-specific and virus replication-dependent. Furthermore, systemic administration of M3 combined with a low dose of cisplatin cured 75% (9/12) of orthotopic hepatic carcinoma mouse models that were otherwise resistant to cisplatin. Our results indicated that the upcoming development in this field would improve the antitumor efficacy and maximize the synergistic effect of oncolytic viruses administered with traditional chemotherapy or radiotherapy.

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“…However, viral replication was not detectable in biopsy specimens, 56 although other clinical trials using ONYX-015 detected viral replication in head and neck cancer, 57,58 ovarian cancer, 59 and in primary and secondary liver metastasis. 60,61 A phase I/II study using ONYX-015 for the treatment of pancreatic cancer was carried out in the Jonsson Comprehensive Cancer Center in Los Angeles, USA. In total, 21 people with pancreatic cancer were eligible for this clinical trial.…”

Section: Onyx-015mentioning

confidence: 99%

The potential of oncolytic virus therapy for pancreatic cancer

et al. 2005

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The objective of this paper was to review a new category of gene therapy using oncolytic viruses for the treatment of pancreatic cancer. The eligibility and feasibility of oncolytic virus therapy as a novel therapeutic agent against pancreatic cancer are discussed as well as basic research for clinical trials, including a historical perspective and the current status of these novel agents. Even combination therapy, such as surgery with radiation and chemotherapy, has not significantly improved the survival rate of pancreatic cancer. Recently, a clinical trial (phase I and II) using an oncolytic adenovirus, ONYX-015, was completed in patients with pancreatic cancer. The phase II trial yielded beneficial results (tumor reduction or stabilization) in about 50% of the patients. A phase I study of the efficacy of oncolytic herpes viruses, G207, OncoVEX GM-CSF, and 1716 against a variety of tumors has been completed, and G207 is in phase II trials for use against brain tumors. In addition, a phase I trial using the herpesvirus showed good tolerance at all dosages. We discuss the basic scientific principles and current results of the above clinical trials with respect to these oncolytic viruses, and then compare the relative advantages and disadvantages of adenoviruses and herpesviruses as oncolytic agents. We also review the published literature on newly developed oncolytic viruses. The concept of oncolytic therapy has been studied for a century. Recent technological developments have made these oncolytic viruses more tumor-specific by exploiting the tumor cell environments. In addition, these viruses have been reported to increase the immunosusceptibility of the tumor cells, and have been designed to express other genes to increase the susceptibility of tumor cells to other therapeutic agents. Oncolytic virus therapy certainly appears to be a feasible treatment for pancreatic cancer.

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E1B-Deleted Adenovirus (dl1520) Gene Therapy for Patients with Primary and Secondary Liver Tumors

Cited by 106 publications

References 17 publications

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Oncolytic adenovirus-mediated transfer of the antisense chk2 selectively inhibits tumor growth in vitro and in vivo

The potential of oncolytic virus therapy for pancreatic cancer

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