Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL

Abstract

We have previously described oncolytic adenovirus (Ad) vectors KD3 and KD3-interferon (IFN) that were rendered cancer-specific by mutations in the E1A region of Ad; these mutations abolish binding of E1A proteins to p300/CBP and pRB. The antitumor activity of the vectors was enhanced by overexpression of the Adenovirus Death Protein (ADP, E3-11.6K) and by replication-linked expression of IFN-a. We hypothesized that the anticancer efficacy of the KD3-IFN vector could be further improved by expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). E1-deleted Ad vectors were constructed carrying reporter genes for enhanced green fluorescent protein or secreted placental alkaline phosphatase (SEAP) and a therapeutic gene for TRAIL under control of the TetON system. Expression of the genes was increased in the presence of a helper virus and the inducer doxycycline such that up to 231-fold activation of expression for the TetON-SEAP vector was obtained. Coinfection with TetON-TRAIL augmented oncolytic activity of KD3 and KD3-IFN in vitro. Induction of TRAIL expression did not reduce the yield of progeny virus. Combination of TetON-TRAIL and KD3-IFN produced superior antitumor activity in vivo as compared with either vector alone demonstrating the efficacy of a four-pronged cancer gene therapy approach, which includes Ad oncolysis, ADP overexpression, IFN-a-mediated immunotherapy, and pharmacologically controlled TRAIL activity.

Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus

“…Effects (9,36,37). Therefore, this model could allow assessing if predosing and pretreatment with warfarin mediate improvements in systemic oncolytic therapy.…”

“…injection of Ad-EGFPLuc is improved by depletion of liver macrophages combined with warfarin pretreatment. Hep3B cells form aggressive, fast-growing tumors in nude mice and are a rigorous model to assess the anticancer activity of oncolytic Ad (9,36,37). To test utility of predosing and warfarin, mice bearing s.c. established Hep3B tumors were pretreated with warfarin or vehicle and predosed with Ad-DsRed-RD or vehicle before injection of 3 Â 10 10 vp of AdEGFPLuc and the tumor growth was monitored.…”

“…Work has been done to increase oncolytic potency of the vectors by arming them with therapeutic genes and has produced promising results (30,(37)(38)(39)(40)(41). However, most of the preclinical and clinical studies with oncolytic Ad have been performed by direct i.t.…”

Tumor-targeted delivery of biologically active TRAIL protein

“…The transfer and expression of TRAIL into cells by adenovirus or adenoassociated virus induces apoptosis and apoptotic bystander effects in several human cancer cells in vitro and in xenograft models of human tumors. [13][14][15] However, adenovirus or adeno-associated virus-based vectors may cause hepatotoxicity through innate and cell-mediated immune responses, and have less targeting to the tumor site when systemically administrated. 16,17 It has been known for more than 60 years that anaerobic bacteria can selectively grow in tumors.…”

Inducible Gene Expression in Tumors Colonized by Modified Oncolytic Vaccinia Virus Strains

“…In bacteria, inducible systems were introduced that could be activated by nontoxic sugar compounds such as L-arabinose (1) and L-rhamnose (2), by tetracycline derivatives (2), or by acetyl salicylic acid (3). Oncolytic adenoviruses have also been equipped with inducible gene expression systems that rely on the administration of tetracycline derivatives (4,5), the absence of theophylline (6), or the application of heat (7). Other oncolytic viruses, however, had not yet been tested in combination with inducible expression systems in tumors.…”