Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity

Abstract

Although genetically engineered adenoviruses hold promise for the treatment of cancer, clinical trial reports have utilized intratumoral injection to date. To determine the feasibility of intravenous delivery of ONYX-015, an E1B-55kD genedeleted replication selective adenovirus with demonstrated clinical safety and antitumoral activity following intratumoral injection, we performed a clinical trial in patients with metastatic solid tumors. ONYX-015 was infused intravenously at escalating doses of 2 × 10 10 to 2 × 10 13 particles via weekly infusion within 21-day cycles in 10 patients with advanced carcinoma metastatic to the lung. No dose-limiting toxicity was identified. Mild to moderate fever, rigors and a dosedependent transient transaminitis were the most common

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

“…[15][16][17][18][19] Some reports have supported the hypothesis that dl1520 selectively kills tumor cells harboring a defective p53 gene, 20,21 while other work by several laboratories found that replication of dl1520 is not determined by p53 status. 18,[22][23][24][25][26] The mechanisms that underlie cancer selective replication of dl1520 are not well characterized.…”

Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector

“…One such vector is ONYX-015 that contains the E1a gene and uses viral genomic deletion for E1b 55k to interrupt the virus life cycle in the presence of cellular p53 (in normal cells) but not mutant p53 (found in many tumor cells). [7][8][9][10] Although ONYX-015 has shown potential in various laboratory and clinical studies, a lack of correlation between p53 status and viral replication has been reported. 15 Other vectors use tumor-specific promoters for E1 gene expression restricted to tumor cells to facilitate viral replication.…”

“…Although the replication-activated adenovirus has been shown to replicate in various human tumor cells, 10 its oncolytic ability and the overall anticancer effect is probably not sufficient to be used alone. Our study indicated that systemic administration of Ad.IR-BG failed to delay tumor growth for both LoVo and SMMC7721 xenografts in nude mice (data not shown).…”

“…Such vectors, that is, ONYX-015 (dl1520) with E1B55-deletion 7 and ONYX-411 containing E1 and E4 genes both under the control of human E2F promoter, 8 have achieved oncolytic effects in various tumors in clinical trials. [8][9][10] Despite this recent progress, adenovirus gene therapy for liver cancer continues to face challenges. Potential limitations include the lack of specific tumor surface markers necessary for viral targeting in liver tumors.…”

Gene therapy for lung neoplasms

“…When used alone, onyx-015 had limited efficacy, though some responses were noted in patients with head and neck cancer. 57,58 Onyx-015 has also been used in combination with Enbrel, a TNF-α antagonist, used to inhibit viral clearance. This study noted suppression of TNF-α secretion with some evidence of reduced viral clearance, but clinical efficacy was limited.…”