Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma

Habib, Nagy; Salama, H. S.; Median, Ahmed Abd El Latif Abu; Anis, Ilia; Aziz, Rasha; Sarraf, Catherine; Mitry, Ragai R.; Havlík, R; Seth, Prem; Hartwigsen, Jack; Bhushan, Reva; Nicholls, Joanna P.; Jensen, S. L.

doi:10.1038/sj.cgt.7700431

Cited by 111 publications

(68 citation statements)

References 20 publications

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“…Those tested in patients have proven to be relatively safe, showing evidence of efficacy. 22,[30][31][32] However, some potentially concerning adverse effects were observed at high doses and most responses detected were transient, suggesting the need for enhancing efficacy. Therefore, further research is required to improve selectivity and, above all, potency of these viruses.…”

Section: Discussionmentioning

confidence: 99%

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

et al. 2009

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The E2F-1 promoter has been used to confer tumorselective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-D24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The D24 deletion avoids a loop of E2F-mediated selfactivation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.

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Section: Discussionmentioning

confidence: 99%

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

et al. 2009

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“…1,36,37 Clinical trials of several hundred patients have shown no evidence of nonspecific viral replication or damage to normal cells at the border of intratumoral injection sites. [38][39][40][41][42][43][44][45][46][47][48][49][50][51] When administered intravenously (i.v. ), dose escalation was limited by transient liver enzyme elevation at a dose of 2 Â 10 13 particles.…”

Section: Onyx 015mentioning

confidence: 99%

“…Furthermore, a 63% response rate was observed, which was greater than the expected response rate of 35% from previous publications in the same patient population using similar chemotherapy regimes. 41 Other clinical investigations of ONYX 015 have involved advanced ovarian cancer, 42 hepatocellular carcinoma, 44 pancreatic cancer 47,49 and colorectal cancer. 48,54 In a meta-analysis 54 summarizing two intrahepatic arterial infusion trials involving colorectal cancer, survival was compared between patients receiving o6 Â 10 11 virus particles per infusion (7 patients) to those receiving 46 Â 10 11 virus particles per infusion (28 patients).…”

Section: Onyx 015mentioning

confidence: 99%

Clinical development directions in oncolytic viral therapy

Eager

Nemunaitis

2011

Cancer Gene Ther

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Oncolytic virotherapy is an emerging experimental treatment platform for cancer therapy. Oncolytic viruses are replicativecompetent viruses that are engineered to replicate selectively in cancer cells with specified oncogenic phenotypes. Multiple DNA and RNA viruses have been clinically tested in a variety of tumors. This review will provide a brief description of these novel anticancer biologics and will summarize the results of clinical investigation. To date oncolytic virotherapy has shown to be safe, and has generated clinical responses in tumors that are resistant to chemotherapy or radiotherapy. The major challenge for researchers is to maximize the efficacy of these viral therapeutics, and to establish stable systemic delivery mechanisms.

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“…32 Conversely, intratumoral, intra-arterial and intravenous administrations of low doses seem well tolerated. 33,34 Several strategies have been approached to circumvent these problems. Adenoviral vectors devoid of viral transactive sequences, the so-called gutless vectors, have been constructed but these vectors remain difficult to produce.…”

Section: Viral Vectorsmentioning

confidence: 99%

“…A partially deleted adenoviral vector that still expresses the E1A protein and induces apoptotic and necrotic mechanisms has been injected into patients without efficient clinical response. 33 The suicide strategy…”

Section: Using Apoptosis To Program the Cell Deathmentioning

confidence: 99%

Gene therapy of hepatocarcinoma: a long way from the concept to the therapeutical impact

Gerolami

Uch²,

Bréchot

et al. 2003

Cancer Gene Ther

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Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma

Cited by 111 publications

References 20 publications

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

Clinical development directions in oncolytic viral therapy

Gene therapy of hepatocarcinoma: a long way from the concept to the therapeutical impact

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