Armed Interference: Oncolytic Viruses Engineered to Carry Antitumor shRNAs

A diverse array of oncolytic viruses are being developed for the treatment of cancer.1Kirn D Martuza RL Zwiebel J Replication-selective virotherapy for cancer: biological principles, risk management and future directions.Nat Med. 2001; 7: 781-787Crossref PubMed Scopus (463) Google Scholar, 2Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumours.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (449) Google Scholar These therapeutic agents are naturally and/or genetically targeted to replicate selectively in cancer cells. The resulting “oncolysis” is a novel mechanism of action (MOA) for cancer treatment and seems in many cases to be effective against apoptosis-resistant cells. In addition to this primary MOA, oncolytic viruses can demonstrate secondary MOAs such as induction of tumor-specific cytotoxic T lymphocytes,3Todo T Rabkin SD Sundaresan P Wu A Meehan KR Herscowitz HB et al.Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus.Hum Gene Ther. 1999; 10: 2741-2755Crossref PubMed Scopus (186) Google Scholar anti-angiogenic cytokines,4Wang Y Hallden G Hill R Brooks G Francis J Kirn D E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models.Nat Biotechnol. 2003; 21: 1328-1335Crossref PubMed Scopus (130) Google Scholar and chemosensitization.5Khuri F Nemunaitis J Ganly I Gore M MacDougal M Tannock I et al.A controlled trial of Onyx-015, an E1B gene-deleted adenovirus, in combination with chemotherapy in patients with recurrent head and neck cancer.Nat Med. 2000; 6: 879-885Crossref PubMed Scopus (997) Google Scholar The next generation of oncolytic viruses have additional MOAs through therapeutic transgene “arming”.6Hermiston T Fighting fire with fire: attacking the complexity of human tumors with armed therapeutic viruses.Curr Opin Mol Ther. 2002; 4: 334-342PubMed Google Scholar These therapeutic payloads are expressed selectively in cancer cells during replication, resulting in complementary MOAs. Examples include JX-594 (targeted vaccinia expressing granulocyte-macrophage colony-stimulating factor (hGM-CSF), Jennerex Biotherapeutics, San Francisco, CA),7Kim JH Oh JY Park BH Lee DE Kim JS Park HE et al.Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF.Mol Ther. 2006; 14: 361-370Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar OncoVex (herpes simplex virus (HSV) expressing hGM-CSF, Biovex, Woburn, MA),8Liu BL Robinson M Han ZQ Branston RH English C Reay P et al.ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties.Gene Ther. 2003; 10: 292-303Crossref PubMed Scopus (549) Google Scholar and MV-NIS (measles virus expressing the sodium iodide symporter gene, Mayo Clinic, Rochester, MN).9Hasegawa K Pham L O'Connor MK Federspiel MJ Russell SJ Peng KW Dual therapy of ovarian cancer using measles viruses expressing carcinoembryonic antigen and sodium iodide symporter.Clin Cancer Res. 2006; 12: 1868-1875Crossref PubMed Scopus (99) Google Scholar In addition, anti-angiogenic and antivascular gene products (e.g., soluble vascular endothelial growth factor receptor (VEGF-R)) have been expressed in the context of a targeted oncolytic virus.10Thorne SH Tam BY Kirn DH Contag CH Kuo CJ Selective intratumoral amplification of an anti-angiogenic vector by an oncolytic virus produces enhanced antivascular and antitumor efficacy.Mol Ther. 2006; 13: 938-946Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Therefore, these armed oncolytic viruses are designed to wage a multipronged attack against cancer. In this issue, Yun and colleagues11Yoo JY Kim J-H Kwon Y-G Kim E-C Kim NK Choi HJ Yun C-O VEGF-specific short hairpin RNA-expressing oncolytic adenovirus elicits potent inhibition of angiogenesis and tumor growth.Mol Ther. 2007; 15: 295-302Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar report proof-of-concept studies on the expression of a small inhibitory RNA (siRNA) from an oncolytic virus. They expressed a small hairpin (sh) RNA against VEGF from an E1A–CR2 gene region–deleted adenovirus (Ad). The authors compared this virus to important controls, including the same oncolytic Ad lacking the shRNA expression cassette and a replication-incompetent Ad expressing the anti-VEGF shRNA. They demonstrated that shRNA expression and anti-VEGF effects were greater and more prolonged in the context of the oncolytic vector as compared with the replication-deficient vector. In addition, the shRNA-armed virus demonstrated superior efficacy over the same virus without shRNA arming. An anti-angiogenic MOA was shown both in vitro and in vivo. Interestingly, the Ad E1A protein also showed anti-VEGF and anti-angiogenic effects. siRNA technologies hold promise for the treatment of cancer. However, thus far this approach has had only limited success in vivo because of several hurdles.12Behlke MA Progress towards in vivo use of siRNAs.Mol Ther. 2006; 13: 644-670Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar These include difficulties in achieving high-level expression selectively in cancers, particularly after intravenous administration. The application of shRNA technology in the context of systemically deliverable oncolytic viruses such as Ads or vaccinia viruses may be particularly effective at overcoming such hurdles. The use of a targeted, armed oncolytic virus to deliver siRNAs has the potential to achieve a higher level of expression in a more tumor-specific fashion than with nonreplicating vector systems. Thus, safety and efficacy should be improved. By combining the shRNA therapeutic platform with the oncolytic virus platform, the promise of both therapeutic platforms may be realized. Several questions remain with this approach. The first is whether suppression of VEGF production from tumor cells will be sufficient to treat human tumors, or whether VEGF production from normal stromal cells and from other proangiogenic factors might prevent an effective anti-angiogenic effect in the tumor. It will also be important to compare different anti-VEGF technologies in the context of an oncolytic virus. Examples include anti-VEGF antibodies (e.g., bevacizumab, Avastin; Genentech, South San Francisco, CA), soluble VEGF-R decoys, and antisense approaches. Because VEGF has immunosuppressive properties, blocking of VEGF activity might result in enhanced immune recognition of tumors and/or the virus itself. Finally, it will be of interest to determine whether the bleeding and gastrointestinal perforation toxicities associated with bevacizumab will be seen with this approach, particularly in the context of oncolysis and the associated inflammation. Answers to these questions will have important implications for this approach and for the field.

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