Elucidation of the molecular mechanism underlying tumor-selective replication of the oncolytic adenovirus mutant ONYX-015.

Tumor-selective replicating viruses offer appealing advantages over conventional cancer therapy. ONYX-015 (dl1520) is the prototype for oncolytic adenoviral therapy. It has undergone extensive clinical testing with proven safety and evidence of promising clinical efficacy. The strategy underlying its tumor-selective cell killing is based on deletion of the viral E1B-55K gene, which is crucial for efficient viral replication in normal cells but dispensable in tumor cells. Originally, the successful replication of ONYX-015 was thought to strictly depend on deregulated p53 signaling in tumor cells. However, recent preclinical as well as clinical evidence questions this mechanism. The study by O'Shea and colleagues is of immense importance as it sheds new light into the molecular mechanism underlying the tumor-selective replication of ONYX-015. Based on these findings, modulation of the proposed molecular mechanism by pharmacologic agents or hyperthermia may largely enhance the therapeutic index of ONYX-015 for tumor cells versus normal tissue and improve clinical efficacy. Finally, new strategies to allow successful patient stratification for future clinical trials appear to be in reach, based on the reported results.