Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer

Replication-selective oncolytic adenoviruses represent a novel cancer treatment platform. Clinical studies have demonstrated the safety and feasibility of the approach, including the delivery of adenovirus to tumors through the bloodstream (Heise et al., 1999b; Reid et al., 1999; Nemunaitis et al., 1999). The inherent ability of replication-competent adenoviruses to sensitize tumor cells to chemotherapy was a novel discovery that has led to chemosensitization strategies. These data will support the further development of adenoviral agents, including second-generation constructs containing exogenous therapeuitc genes to enhance both local and systemic antitumoral activity (Heise and Kirn, 2000; Hermiston, 2000; Agha-Mohammadi and Lotze, 2000). In addition to adenovirus, other viral species are being developed including herpesvirus, vaccinia, reovirus and measles virus (Kirn, 2000a; Martuza, 2000; Norman and Lee, 2000; Mastrangelo et al., 2000; Coffey et al., 1998; Martuza et al., 1991; Kirn, 2000b; Lattime et al., 1996). Since intratumoral spread also appears to be a substantial hurdle for viral agents, inherently motile agents such as bacteria may hold great promise for this field (Low et al., 1999; Sznol et al., 2000). Given the unknown predictive value of in vitro cell-based assays and murine tumor model systems for the efficacy and therapeutic index of replication-selective oncolytic adenoviruses in patients, we believe that encouraging adenoviral agents must be tested in well-designed clinical trials as soon as possible. Only then can the true therapeutic potential of these agents be realized.