Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded

Abstract

Virotherapy is currently undergoing a renaissance, based on our improved understanding of virus biology and genetics and our better knowledge of many different types of cancer. Viruses can be reprogrammed into oncolytic vectors by combining three types of modification: targeting, arming and shielding. Targeting introduces multiple layers of cancer specificity and improves safety and efficacy; arming occurs through the expression of prodrug convertases and cytokines; and coating with polymers and the sequential usage of different envelopes or capsids provides shielding from the host immune response. Virus-based therapeutics are beginning to find their place in cancer clinical practice, in combination with chemotherapy and radiation.

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

“…Tumor size was measured using a caliper, and tumor volume was calculated using the formula: length  width 2 /2. Mice were killed when tumor volume reached 1500 mm 3 . Unpaired t-test and log-rank statistical analyses were performed on growth curve and Kaplan-Meier survival graph using Prism 4 (GraphPad, San Diego, CA).…”

“…1,2 OVs exploit genetic abnormalities and altered signaling pathways in tumor cells to achieve selective virus replication and tumor cell lysis. 3 Vesicular Stomatitis Virus (VSV) is a negative single-stranded RNA virus that has served as an important prototype OV. VSV is exquisitely sensitive to type 1 interferon-mediated antiviral responses in untransformed cells, and consequently its selective oncotropism is attributed to the innate antiviral response suppression in tumor cells.…”

Anticancer Gene Transfer for Cancer Gene Therapy

“…In addition to targeting, strategies are often employed to amplify the cytolytic capabilities of oncolytic viruses to increase their efficacy. This process was named "oncolytic arming" since a transgene is helping the innate cytotoxic ability of a virus (Cattaneo et al, 2008). Arming of a virus requires a careful selection of a viral vector that will be used as oncolytic agent and can be achieved through three major strategies that are discussed below and are: pro-drug oncolytic arming, pro-apoptotic gene arming and microenvironment-regulation-able gene arming.…”

“…These efforts resulted in the first generation of the viruses that has been used extensively that utilized the native ability of the virus to enter a lytic cycle and also to be targeted to cancer cells specifically using advanced molecular engineering. We are now able to visualize the spread of the viruses using reporter genes and evaluate the efficacy of each virus in a specific biological system (Doyle et al, 2004;Piwnica-Worms et al, 2004;Peng et al, 2006;Cattaneo et al, 2008).…”

Artificial riboswitches for gene expression and replication control of DNA and RNA viruses

“…Thus, a drug-inducible safety switch is a valuable tool to facilitate therapeutic applications of virus strains for which pathogenicity is of concern (refs. 2, 3, and references therein) and of new generations of oncolytic viruses that were engineered for enhanced potency by different strategies for which side effects in patients cannot be predicted (1,4). Furthermore, transient immunosuppression is being investigated as a means to block antiviral immunity thereby enhancing oncolysis (5).…”