Oncolytic viral therapy for human cancer: Challenges revisited

Abstract

Conditional replicative, oncolytic adenoviruses are genetically modified to replicate primarily in malignant cells with oncogenetic defects, selectively killing cancer cells in the process. Viral progenies released within the tumor microenvironment can penetrate, infect, and destroy additional cell layers of the solid tumor mass. Much excitement has been generated over the clinical successes of ONYX-015 adenovirus treatment for advanced head and neck cancer, pancreatic carcinoma, and metastatic colorectal carcinoma at the locoregional level. However, follow-up trials with systemic viral administration have not met initial expectations. This review examines recent basic science developments that may potentially overcome the two key limitations of systemic virotherapy, namely, suboptimal tumor oncolysis and pharmacokinetic shortcomings due to rapid viral clearance. Late-generation constructs incorporate alternative viral backbone modifications and antitumor transgenes to enhance oncolytic potency. Furthermore, altered viral tropism, through masking or substitution of viral surface components, is likely to promote tumor-selective targeting and safety. Merits of these approaches in the clinical arena are discussed. Drug Dev.

Antitumor Activity of an Oncolytic Adenovirus-Delivered Oncogene Small Interfering RNA

“…The finding of Internavec (and ONYX-411) replication in HMEC cells with an intact pRb pathway, albeit at a markedly lower level as compared with dl309, likely reflects viral replication in the growth fraction of these nonmalignant cells that releases E2F-1 through physiologic phosphorylation of retinoblastoma after entry into the cell cycle. Nonetheless, the limited proliferative activity of normal cells in vivo is expected to foster minimal viral replication and cytotoxicity in nonmalignant tissues (13,14,(16)(17)(18), because E1 and E4 expression of Internavec is under the control of an E2F-1 promoter (16).…”

“…Host cells with viral protein expression are commonly seen post-infection, indicative of an aborted viral replicative process and/or a latent infection state (13,28,29). Coupled with the common defects in apoptotic and IFN-induction pathways in cancer cells, the aborted oncolytic process is an explanation for incomplete clinical responses seen in oncolytic virotherapy trials (14,18). The incorporation of a regulatory siRNA transgene that can disrupt cell survival mechanisms, such as through K-ras knockdown, could conceivably tilt the cellular balance towards cancer cell death.…”

“…Our proof-of-principle study also suggests that the oncolytic virus may be used to deliver siRNAs directed against other oncogene sequences that critically contribute to cancer cell growth. The strategy of incorporating multiple, tandem siRNAs with distinct knockdown specificities could conceivably address the issues of tumor phenotypic heterogeneity and the development of resistance to siRNA knockdown from single base pair mutations (18).…”

“…Therapeutic doses (up to 10 12 viral particles) of ONYX-015 and other oncolytic adenoviruses are well tolerated (reviewed in ref. 14), and have produced clinical efficacy at the locoregional level, particularly in advanced head and neck cancer (14,17,18).…”

Cancer Gene Therapy via NKG2D and FAS Pathways

“…Recently, conditional replicative oncolytic adenoviruses have been shown to replicate and kill tumor cells without harming normal cells. The tumor specificity of these viruses has been manifested through the incorporation of tissue or tumor specific promoters that limit viral gene (Tong, 2006;Gomes and Tong, 2006). A recent study indicates that the use of adenoviral vectors for clinical gene therapy is widespread.…”