Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-Δ24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer

Page, John G.; Tian, Baohong; Schweikart, Karen; Tomaszewski, Joseph E.; Harris, Ray; Broadt, Trevor; Polley-Nelson, Judith; Noker, Patricia E.; Wang, Minghui; Makhija, Sonia K.; Aurigemma, Rosemarie; Curiel, David T.; Alvarez, Ronald D.

doi:10.1016/j.ajog.2006.12.016

Cited by 32 publications

(32 citation statements)

References 27 publications

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“…In summary, VCN-01 toxicology data obtained in the preclinical studies are similar to the previously described for ICOVIR-15, ICOVIR-15K, and ICOVIR-17 (12,21) and detected alterations match with the most common toxicity events reported after systemic administration of adenoviruses in clinical trials (35)(36)(37)41). Biodistribution studies were consistent with the toxicology pattern, with highest levels of viral genomes in the liver at early time points, in agreement with previous reports (32,(42)(43)(44)(45). However, at later time points only residual traces of viral DNA were observed in liver as well as in other nontarget organs.…”

Section: Discussionsupporting

confidence: 79%

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Rodríguez-García

Giménez-Alejandre

Rojas

et al. 2015

Clinical Cancer Research

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Purpose: Tumor targeting upon intravenous administration and subsequent intratumoral virus dissemination are key features to improve oncolytic adenovirus therapy. VCN-01 is a novel oncolytic adenovirus that combines selective replication conditional to pRB pathway deregulation, replacement of the heparan sulfate glycosaminoglycan putative-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK for tumor targeting, and expression of hyaluronidase to degrade the extracellular matrix. In this study, we evaluate the safety and efficacy profile of this novel oncolytic adenovirus.Experimental Design: VCN-01 replication and potency were assessed in a panel of tumor cell lines. VCN-01 tumor-selective replication was evaluated in human fibroblasts and pancreatic islets. Preclinical toxicity, biodistribution, and efficacy studies were conducted in mice and Syrian hamsters.Results: Toxicity and biodistribution preclinical studies support the selectivity and safety of VCN-01. Antitumor activity after intravenous or intratumoral administration of the virus was observed in all tumor models tested, including melanoma and pancreatic adenocarcinoma, both in immunodeficient mice and immunocompetent hamsters.Conclusions: Oncolytic adenovirus VCN-01 characterized by the expression of hyaluronidase and the RGD shaft retargeting ligand shows an efficacy-toxicity prolife in mice and hamsters by intravenous and intratumoral administration that warrants clinical testing.

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Section: Discussionsupporting

confidence: 79%

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Rodríguez-García

Giménez-Alejandre

Rojas

et al. 2015

Clinical Cancer Research

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“…Several of these mutants target the pRb/p16 pathway by deletion of the small E1ACR2 domain, essential for pRb binding and inactivation, and S-phase entry to support viral replication and propagation. [21][22][23] The pRb/p16 pathway is deregulated in the majority of cancers including most pancreatic tumors and consequently replication can proceed in tumor but not in normal cells with intact cell cycle control. 24,25 The E1ACR2-deleted oncolytic adenoviral mutants have superior efficacy compared with ONYX-015 in numerous in vivo cancer models.…”

Section: Introductionmentioning

confidence: 99%

The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

et al. 2011

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Pancreatic adenocarcinomas are aggressive and frequently develop resistance to all current therapies. Replication-selective adenoviruses can overcome resistance to chemotherapeutics through their sensitizing effects on drug-induced cell killing. We previously found that adenovirus deleted in the anti-apoptotic E1B19K gene enhanced gemcitabine-induced apoptotis. Here we demonstrate that our engineered double-deleted AdDD mutant (deleted in the pRb-binding E1ACR2 region and E1B19K) selectively replicates and enhances cell killing in combination with DNA-damaging cytotoxic drugs in pancreatic cancer cells. Combinations of AdDD with gemcitabine, irinotecan or cisplatin resulted in two-to fourfold decreases in EC 50 (half maximal effective concentration) values and was more efficent than similar combinations with wild-type virus, the dl1520 (ONYX-015) and dl922-947 mutants. AdDD replication was impaired in normal bronchial human epithelial cells and did not sensitize the cells to drugs. Gemcitabine-insensitive AsPC-1, BxPC-3 and PANC-1 cells were efficiently killed by irinotecan in combination with AdDD. Suboptimal doses of AdDD and gemcitabine significantly prolonged time to tumor progression in two human pancreatic tumor xenograft in vivo models, PT45 and SUIT-2. We conclude that AdDD has low toxicity to normal cells while potently sensitizing pancreatic cancer cells to DNA-damaging drugs, and holds promise as an improved therapeutic strategy for pancreatic cancer.

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“…13,14,21 More recently, oncolytic viruses with improved potency have been engineered, such as the E1ACR2-deleted mutants dl922-947 and AdD24. [22][23][24] The E1ACR2 region is essential for viral replication in normal cells through binding and inactivating of pRb forcing the S-phase entry to support viral replication. The majority of pancreatic adenocarcinomas have deregulated cell cycle control that complements the lack of E1A binding to pRb and allows viral production to proceed.…”

Section: Introductionmentioning

confidence: 99%

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

et al. 2011

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Pancreatic adenocarcinoma has a poor prognosis and frequently develops resistance to standard chemotherapeutics. Oncolytic adenoviruses represent a promising approach to overcome treatment resistance. The replication-selective dl922-947 adenovirus, defective in pRb binding, targets cancers with deregulated cell cycle control, such as the majority of pancreatic tumors. Cell killing efficacy was higher for dl922-947 than for adenovirus type 5 (Ad5) and the clinically approved dl1520 in pancreatic cancer cells with K-ras, p16 and p53 mutations. Combinations of dl922-947 and 5-fluorouracil or gemcitabine (2resulted in strong synergistic cell killing in Suit-2 and the highly drug-and virus-resistant Hs766T cells. Viral uptake increased in response to drugs, but was independent of the expression levels of the viral attachment receptor coxsackie and adenovirus receptor (CAR), whereas expression levels of the internalization receptors a v b 3 -and a v b 5 -integrins were increased. Early viral E1A expression was potently induced with drugs contributing to the synergistic effects. The dl922-947 mutant was more efficacious than Ad5 in vivo in Hs766T and Suit-2 xenograft models. In combination with gemcitabine, median survival was further prolonged. We demonstrate that dl922-947 is highly efficacious in pancreatic cancers and conclude that oncolytic adenoviruses harboring the E1ACR2 deletion have great potential for development into future clinical candidates for pancreatic cancer.

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Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-Δ24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer

Cited by 32 publications

References 27 publications

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

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