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

Abstract

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.

A Novel CDC25B Promoter–Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models

“…Several CRAds have been evaluated in preclinical trials for their potential therapeutic effect on pancreatic cancer such as the cyclooxygenase 2 promoter-based CRAd (6), and especially the hTERT promoter-based CRAd (7). Several preclinical studies have demonstrated improved efficacy when hTERT-or COX-2-promoter-based oncolytic adenovirus (OAV), were combined with gemcitabine (6,8); the replication-selective dl922-947 adenovirus, defective in pRb binding, improved mice survival when combined with 5-FU and gemcitabine (9). At the clinical level it was of note that intratumorally injected ONYX-15 OV combined with gemcitabine was well-tolerated in a phase I/II clinical trial of patients with pancreatic cancer (10).…”

The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

“…We have previously demonstrated that the Suit-2 model is suitable for determining efficacy of adenoviral mutants administered alone or in combination with cytotoxic drugs (12,41). Both Adwt and Ad5-3D-A20T potently prevented tumor growth up to 20 days after the first administration of virus (Fig.…”

Histone deacetylase inhibitor trichostatin A enhances the antitumor effect of the oncolytic adenovirus H101 on esophageal squamous cell carcinoma in vitro and in vivo

“…However, clinical trials in patients with head and neck cancer have revealed that the efficacy of this treatment is limited when it is utilized as a single modality, potentially due to inefficient intratumoral viral dispersal and the barriers imposed by the tumor microenvironment (15). Therefore, oncolytic Ads H101 requires combination with another modality to improve its antitumor activity (9,14,(16)(17)(18).…”