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  • Review Article
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Recent progress in the battle between oncolytic viruses and tumours

Key Points

  • Clinical trials have indicated that oncolytic viruses might be developed as safe and effective anticancer agents.

  • The translation of oncolytic viruses from the culture dish to preclinical tumour models to studies involving patients has revealed new hurdles to cancer therapy that can be overcome using multidisciplinary approaches.

  • Novel strategies can be used to facilitate viral evasion of the immune system, the prevention of viral uptake by the liver, and an increased specificity for tumour cells, either at the cell surface or through intracellular restriction.

  • Oncolytic viruses can be engineered to target the same genetic mutations that provide tumour cells with a proliferative or survival advantage in patients.

  • The intravenous delivery of viruses must be perfected if oncolytic virus-based therapeutics are to be used to treat patients with metastatic tumours.

Abstract

In the past 5 years, the field of oncolytic virus research has matured significantly and is moving past the stage of being a laboratory novelty into a new era of preclinical and clinical trials. What have recent anticancer trials of oncolytic viruses taught us about this exciting new line of therapeutics?

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Figure 1: Infection and killing of tumour cells by an oncolytic virus.
Figure 2: Barriers to optimal delivery of oncolytic viruses to tumours in vivo.

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References

  1. De Pace, N. G. Sulla scomparsa di un enorme cancro vegetante del callo dell'utero senza cura chirurgica. Ginecologia 9, 82–88 (1912).

    Google Scholar 

  2. Dock, G. Rabies virus vaccination in a patient with cervical carcinoma. Amer. J. Med. Sci. b127 (1904).

  3. Viral Therapy of Human Cancers (eds Sinkovics, J. G & Horvath, J. C.) (Taylor and Francis CRC, Baco Raton, 2004).

  4. Benencia, F. et al. HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer. Mol. Ther. 12, 789–802 (2005) (10.1016/j.ymthe.2005.03.026).

    Article  CAS  PubMed  Google Scholar 

  5. Xia, Z. J. et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng 23, 1666–1670 (2004).

    PubMed  Google Scholar 

  6. Shah, A. C., Benos, D., Gillespie, G. Y. & Markert, J. M. Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J. Neurooncol. 65, 203–226 (2003).

    PubMed  Google Scholar 

  7. Kaufman, H. L. et al. Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J. Clin. Invest. 115, 1903–1912 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Chiocca, E. A. et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol. Ther. 10, 958–966 (2004).

    CAS  PubMed  Google Scholar 

  9. Harrow, S. et al. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther. 11, 1648–1658 (2004).

    CAS  PubMed  Google Scholar 

  10. Markert, J. M. et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 7, 867–874 (2000).

    CAS  PubMed  Google Scholar 

  11. Khuri, F. R. et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nature Med. 6, 879–885 (2000).

    CAS  PubMed  Google Scholar 

  12. Heise, C. et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Med. 3, 639–645 (1997).

    CAS  PubMed  Google Scholar 

  13. O'Shea, C. C., Soria, C., Bagus, B. & McCormick, F. Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell 8, 61–74 (2005).

    CAS  PubMed  Google Scholar 

  14. Reid, T., Warren, R. & Kirn, D. Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther. 9, 979–986 (2002). This review describes some of the unique properties that are associated with oncolytic virus therapy.

    CAS  PubMed  Google Scholar 

  15. Lorence, R. M. et al. Overview of phase I studies of intravenous administration of PV701, an oncolytic virus. Curr. Opin. Mol. Ther. 5, 618–624 (2003).

    CAS  PubMed  Google Scholar 

  16. Pecora, A. L. et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J. Clin. Oncol. 20, 2251–2266 (2002).

    CAS  PubMed  Google Scholar 

  17. Lorence, R. M. et al. Continuing the interaction between non-clinical and clinical studies. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (12 Mar 2005).

    Google Scholar 

  18. Reid, T. et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Ther. 8, 1618–1626 (2001).

    CAS  PubMed  Google Scholar 

  19. Taneja, S., MacGregor, J., Markus, S., Ha, S. & Mohr, I. Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells. Proc. Natl Acad. Sci. USA 98, 8804–8808 (2001).

    CAS  PubMed  Google Scholar 

  20. Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Dorig, R. E., Marcil, A., Chopra, A. & Richardson, C. D. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 75, 295–305 (1993).

    CAS  PubMed  Google Scholar 

  22. Hsu, E. C., Iorio, C., Sarangi, F., Khine, A. A. & Richardson, C. D. CDw150(SLAM) is a receptor for a lymphotropic strain of measles virus and may account for the munosuppressive properties of this virus. Virology 279, 9–21 (2001).

    CAS  PubMed  Google Scholar 

  23. Tatsuo, H., Ono, N., Tanaka, K. & Yanagi, Y. The cellular receptor for measles virus: SLAM (CDw150). Uirusu 50, 289–296 (in Japanese) (2000).

    CAS  PubMed  Google Scholar 

  24. Schneider, U., Bullough, F., Vongpunsawad, S., Russell, S. J. & Cattaneo, R. Recombinant measles viruses efficiently entering cells through targeted receptors. J. Virol. 74, 9928–9936 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hammond, A. L. et al. Single-chain antibody displayed on a recombinant measles virus confers entry through the tumor-associated carcinoembryonic antigen. J. Virol. 75, 2087–2096 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bucheit, A. D. et al. An oncolytic measles virus engineered to enter cells through the CD20 antigen. Mol. Ther. 7, 62–72 (2003).

    CAS  PubMed  Google Scholar 

  27. Peng, K. W. et al. Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. Blood 101, 2557–2562 (2003).

    CAS  PubMed  Google Scholar 

  28. Hahm, B. et al. Measles virus infects and suppresses proliferation of T lymphocytes from transgenic mice bearing human signaling lymphocytic activation molecule. J. Virol. 77, 3505–3515 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Vongpunsawad, S., Oezgun, N., Braun, W. & Cattaneo, R. Selectively receptor-blind measles viruses: identification of residues necessary for SLAM- or CD46-induced fusion and their localization on a new hemagglutinin structural model. J. Virol. 78, 302–313 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nakamura, T. et al. Antibody-targeted cell fusion. Nature Biotechnol. 22, 331–336 (2004).

    CAS  Google Scholar 

  31. Russell, S. Retargeting, attachment and entry of oncolytic viruses. American Society of Gene Therapy Meeting: St. Louis (2005).

    Google Scholar 

  32. Yu, D. C., Chen, Y., Seng, M., Dilley, J. & Henderson, D. R. The addition of adenovirus type 5 region E3 enables calydon virus 787 to eliminate distant prostate tumor xenografts. Cancer Res. 59, 4200–4203 (1999). Description of a transcriptionally regulated adenovirus for the treatment of patients with prostate cancer.

    CAS  PubMed  Google Scholar 

  33. O'Shea, C. C. et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 6, 611–623 (2004). Clarification of the mechanism of action of the Onyx-015 virus.

    CAS  PubMed  Google Scholar 

  34. Bergelson, J. M. et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323 (1997).

    CAS  PubMed  Google Scholar 

  35. Douglas, J. T. et al. Targeted gene delivery by tropism-modified adenoviral vectors. Nature Biotechnol. 14, 1574–1578 (1996).

    CAS  Google Scholar 

  36. Shayakhmetov, D. M., Li, Z. Y., Ni, S. & Lieber, A. Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors. J. Virol. 78, 5368–5381 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kawakami, Y. et al. Substitution of the adenovirus serotype 5 knob with a serotype 3 knob enhances multiple steps in virus replication. Cancer Res. 63, 1262–1269 (2003).

    CAS  PubMed  Google Scholar 

  38. Breidenbach, M. et al. Genetic replacement of the adenovirus shaft fiber reduces liver tropism in ovarian cancer gene therapy. Hum. Gene Ther. 15, 509–518 (2004).

    CAS  PubMed  Google Scholar 

  39. Nilsson, M. et al. Development of an adenoviral vector system with adenovirus serotype 35 tropism; efficient transient gene transfer into primary malignant hematopoietic cells. J. Gene Med. 6, 631–641 (2004).

    CAS  PubMed  Google Scholar 

  40. Dmitriev, I. et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J. Virol. 72, 9706–9713 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Borovjagin, A. V. et al. Complex mosaicism is a novel approach to infectivity enhancement of adenovirus type 5-based vectors. Cancer Gene Ther. 12, 475–486 (2005).

    CAS  PubMed  Google Scholar 

  42. Maisner, A. et al. Recombinant measles virus requiring an exogenous protease for activation of infectivity. J. Gen. Virol. 81, 441–449 (2000).

    CAS  PubMed  Google Scholar 

  43. Cattaneo, R. Defining tropism of oncolytic vectors by protease availability: measles viruses selectively fusing matrix-metalloproteinase expressing cells. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (12 Mar 2005).

    Google Scholar 

  44. Alain, T. et al. Oncolysis by reovirus intermediate subviral particles. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (12 Mar 2005).

    Google Scholar 

  45. Van Themsche, C., Potworowski, E. F. & St. Pierre, Y. Stromelysin-1 (MMP-3) is inducible in T lymphoma cells and accelerates the growth of lymphoid tumors in vivo. Biochem. Biophys. Res. Commun. 315, 884–891 (2004).

    CAS  PubMed  Google Scholar 

  46. Au, G. G., Lindberg, A. M., Barry, R. D. & Shafren, D. R. Oncolysis of vascular malignant human melanoma tumors by Coxsackievirus A21. Int. J. Oncol. 26, 1471–1476 (2005). Characterization of the oncolytic activity of coxsackievirus.

    CAS  PubMed  Google Scholar 

  47. Shafren, D. R., Sylvester, D., Johansson, E. S., Campbell, I. G. & Barry, R. D. Oncolysis of human ovarian cancers by echovirus type 1. Int. J. Cancer 115, 320–328 (2005).

    CAS  PubMed  Google Scholar 

  48. Gromeier, M., Lachmann, S., Rosenfeld, M. R., Gutin, P. H. & Wimmer, E. Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc. Natl Acad. Sci. USA 97, 6803–6808 (2000). First description of a poliovirus as an oncolytic virus.

    CAS  PubMed  Google Scholar 

  49. Gromeier, M. et al. The human poliovirus receptor. Receptor-virus interaction and parameters of disease specificity. Ann. NY Acad. Sci. 753, 19–36 (1995).

    CAS  PubMed  Google Scholar 

  50. Ochiai, H. et al. Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus. Clin. Cancer Res. 10, 4831–4838 (2004).

    CAS  PubMed  Google Scholar 

  51. Nakamura, T. et al. Rescue and propagation of fully retargeted oncolytic measles viruses. Nature Biotechnol. 23, 209–214 (2005). Describes a unique approach that could be used to target many different kinds of enveloped viruses. The first description of a replication competent re-targeted virus that is not compromised in its ability to grow to high titres.

    CAS  Google Scholar 

  52. Peng, K. W. Measles virus imaging and tumour targeting. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (12 Mar 2005).

  53. Ohno, S., Ono, N., Takeda, M., Takeuchi, K. & Yanagi, Y. Dissection of measles virus V protein in relation to its ability to block α/β interferon signal transduction. J. Gen. Virol. 85, 2991–2999 (2004).

    CAS  PubMed  Google Scholar 

  54. Sana, T. R., Janatpour, M. J., Sathe, M., McEvoy, L. M. & McClanahan, T. K. Microarray analysis of primary endothelial cells challenged with different inflammatory and immune cytokines. Cytokine 29, 256–269 (2005).

    CAS  PubMed  Google Scholar 

  55. Chawla-Sarkar, M. et al. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 8, 237–249 (2003).

    CAS  PubMed  Google Scholar 

  56. de Veer, M. J. et al. Functional classification of interferon-stimulated genes identified using microarrays. J. Leukoc. Biol. 69, 912–920 (2001).

    CAS  PubMed  Google Scholar 

  57. Khabar, K. S. et al. Expressed gene clusters associated with cellular sensitivity and resistance towards anti-viral and anti-proliferative actions of interferon. J. Mol. Biol. 342, 833–846 (2004).

    CAS  PubMed  Google Scholar 

  58. Dunn, G. P. et al. A critical function for type I interferons in cancer immunoediting. Nature Immunol. 6, 722–729 (2005).

    CAS  Google Scholar 

  59. Ikeda, H., Old, L. J. & Schreiber, R. D. The roles of IFN γ in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev. 13, 95–109 (2002). A very nice review of the data supporting the idea that immunosurveillance is an important factor in tumour evolution.

    CAS  PubMed  Google Scholar 

  60. Stojdl, D. F. et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nature Med. 7, 821–825 (2000).

    Google Scholar 

  61. Stojdl, D. F. et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4, 263–275 (2003).

    CAS  PubMed  Google Scholar 

  62. Faria, P. A. et al. VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway. Mol. Cell 17, 93–102 (2005).

    CAS  PubMed  Google Scholar 

  63. Wang, F. et al. Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nature Immunol. 5, 1266–1274 (2004). First description of how the tropism of the myxoma poxvirus is regulated by components of the innate antiviral response.

    CAS  Google Scholar 

  64. Ahmed, M., Cramer, S. D. & Lyles, D. S. Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses. Virology 330, 34–49 (2004).

    CAS  PubMed  Google Scholar 

  65. Shinozaki, K., Ebert, O. & Woo, S. L. Eradication of advanced hepatocellular carcinoma in rats via repeated hepatic arterial infusions of recombinant VSV. Hepatology 41, 196–203 (2005).

    PubMed  Google Scholar 

  66. Balachandran, S., Porosnicu, M. & Barber, G. N. Oncolytic activity of vesicular stomatitis virus is effective against tumors exhibiting aberrant p53, Ras, or myc function and involves the induction of apoptosis. J. Virol. 75, 3474–3479 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Park, M. S., Garcia-Sastre, A., Cros, J. F., Basler, C. F. & Palese, P. Newcastle disease virus V protein is a determinant of host range restriction. J. Virol. 77, 9522–9532 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Muster, T. et al. Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants. Int. J. Cancer 110, 15–21 (2004).

    CAS  PubMed  Google Scholar 

  69. Bjornsti, M. A. & Houghton, P. J. Lost in translation: dysregulation of cap-dependent translation and cancer. Cancer Cell 5, 519–523 (2004). A brief but excellent review of the importance of translation regulation and cancer.

    CAS  PubMed  Google Scholar 

  70. Huang, S. & Houghton, P. J. Targeting mTOR signaling for cancer therapy. Curr. Opin. Pharmacol. 3, 371–377 (2003).

    CAS  PubMed  Google Scholar 

  71. Perkins, D. J. & Barber, G. N. Defects in translational regulation mediated by the α subunit of eukaryotic initiation factor 2 inhibit antiviral activity and facilitate the malignant transformation of human fibroblasts. Mol. Cell. Biol. 24, 2025–2040 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Topisirovic, I. et al. Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels. Mol. Cell. Biol. 25, 1100–1112 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Clemens, M. J. Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene 23, 3180–3188 (2004).

    CAS  PubMed  Google Scholar 

  74. Kaempfer, R. RNA sensors: novel regulators of gene expression. EMBO Rep. 4, 1043–1047 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Mulvey, M., Poppers, J., Sternberg, D. & Mohr, I. Regulation of eIF2α phosphorylation by different functions that act during discrete phases in the herpes simplex virus type 1 life cycle. J. Virol. 77, 10917–10928 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Rivas-Estilla, A. M. et al. PKR-dependent mechanisms of gene expression from a subgenomic hepatitis C virus clone. J. Virol. 76, 10637–10653 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Farassati, F., Yang, A. D. & Lee, P. W. Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1. Nature Cell Biol. 3, 745–750 (2001).

    CAS  PubMed  Google Scholar 

  78. Balachandran, S. & Barber, G. N. Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell 5, 51–65 (2004). First report of the ability of an oncolytic virus to exploit tumour cell defects in the regulation of translation.

    CAS  PubMed  Google Scholar 

  79. Langland, J. O. & Jacobs, B. L. Inhibition of PKR by vaccinia virus: role of the N- and C-terminal domains of E3L. Virology 324, 419–429 (2004).

    CAS  PubMed  Google Scholar 

  80. Gerotto, M. et al. Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon. Gastroenterology 119, 1649–1655 (2000).

    CAS  PubMed  Google Scholar 

  81. He, B., Gross, M. & Roizman, B. The γ134.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1α to dephosphorylate the α subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc. Natl Acad. Sci. USA 94, 843–848 (1997).

    CAS  PubMed  Google Scholar 

  82. Mineta, T., Rabkin, S. D., Yazaki, T., Hunter, W. D. & Martuza, R. L. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nature Med. 1, 938–943 (1995).

    CAS  PubMed  Google Scholar 

  83. Chahlavi, A., Todo, T., Martuza, R. L. & Rabkin, S. D. Replication-competent herpes simplex virus vector G207 and cisplatin combination therapy for head and neck squamous cell carcinoma. Neoplasia 1, 162–169 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mashour, G. A. et al. Therapeutic efficacy of G207 in a novel peripheral nerve sheath tumor model. Exp. Neurol. 169, 64–71 (2001).

    CAS  PubMed  Google Scholar 

  85. Sundaresan, P., Hunter, W. D., Martuza, R. L. & Rabkin, S. D. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J. Virol. 74, 3832–3841 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Toda, M., Rabkin, S. D., Kojima, H. & Martuza, R. L. Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. Hum. Gene Ther. 10, 385–393 (1999).

    CAS  PubMed  Google Scholar 

  87. Martuza, R. L., Malick, A., Markert, J. M., Ruffner, K. L. & Coen, D. M. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252, 854–856 (1991). First description of an engineered, replicating virus for oncolytic therapy.

    CAS  PubMed  Google Scholar 

  88. Takaoka, A. et al. Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516–523 (2003).

    CAS  PubMed  Google Scholar 

  89. Munoz-Fontela, C. et al. Resistance to viral infection of super p53 mice. Oncogene 24, 3059–3062 (2005).

    CAS  PubMed  Google Scholar 

  90. Balachandran, S. & Barber, G. N. Vesicular stomatitis virus (VSV) therapy of tumors. IUBMB Life 50, 135–138 (2000).

    CAS  PubMed  Google Scholar 

  91. Lee, C. J., Liao, C. L. & Lin, Y. L. Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection. J. Virol. 79, 8388–8399 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Reboredo, M., Greaves, R. F. & Hahn, G. Human cytomegalovirus proteins encoded by UL37 exon 1 protect infected fibroblasts against virus-induced apoptosis and are required for efficient virus replication. J. Gen. Virol. 85, 3555–3567 (2004).

    CAS  PubMed  Google Scholar 

  93. Wright, C. W., Means, J. C., Penabaz, T. & Clem, R. J. The baculovirus anti-apoptotic protein Op-IAP does not inhibit drosophila caspases or apoptosis in drosophila S2 cells and instead sensitizes S2 cells to virus-induced apoptosis. Virology 335, 61–71 (2005).

    CAS  PubMed  Google Scholar 

  94. Liu, T. C. et al. An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency. Mol. Ther. 9, 786–803 (2004).

    CAS  PubMed  Google Scholar 

  95. Shelton, J. G. et al. The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what's genetics got to do with it? Expert Opin. Ther. Targets 9, 1009–1030 (2005).

    CAS  PubMed  Google Scholar 

  96. McCart, J. A. et al. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 61, 8751–8757 (2001).

    CAS  PubMed  Google Scholar 

  97. Garcia, M. A., Guerra, S., Gil, J., Jimenez, V. & Esteban, M. Anti-apoptotic and oncogenic properties of the dsRNA-binding protein of vaccinia virus, E3L. Oncogene 21, 8379–8387 (2002).

    CAS  PubMed  Google Scholar 

  98. Bessis, N., GarciaCozar, F. J. & Boissier, M. C. Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther. 11 (suppl.), S10–S17 (2004).

    CAS  PubMed  Google Scholar 

  99. Hirasawa, K. et al. Systemic reovirus therapy of metastatic cancer in immune-competent mice. Cancer Res. 63, 348–353 (2003).

    CAS  PubMed  Google Scholar 

  100. Thorne, S. The design and testing of oncolytic vaccinia virus vectors for efficient systemic delivery of transgenes. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (11 Mar 2005).

  101. Ichihashi, Y. Extracellular enveloped vaccinia virus escapes neutralization. Virology 217, 478–485 (1996).

    CAS  PubMed  Google Scholar 

  102. Law, M. & Smith, G. L. Antibody neutralization of the extracellular enveloped form of vaccinia virus. Virology 280, 132–142 (2001).

    CAS  PubMed  Google Scholar 

  103. Fisher, K. D. et al. Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies. Gene Ther. 8, 341–348 (2001).

    CAS  PubMed  Google Scholar 

  104. Green, N. K. et al. Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Ther. 11, 1256–1263 (2004). Identifies many of the problems that viral therapeutics face, and novel delivery approaches to overcome these hurdles.

    CAS  PubMed  Google Scholar 

  105. Seymour, L. Systemic delivery of adenovirus: use of polymers to mask unwanted infection and enable intravenous delivery. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (10 Mar 2005).

  106. Ikeda, K. et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nature Med. 5, 881–887 (1999).

    CAS  PubMed  Google Scholar 

  107. Ilan, Y. et al. Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat. Hepatology 26, 949–956 (1997).

    CAS  PubMed  Google Scholar 

  108. Jooss, K., Yang, Y. & Wilson, J. M. Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung. Hum. Gene Ther. 7, 1555–1566 (1996).

    CAS  PubMed  Google Scholar 

  109. Kuriyama, S. et al. Transient cyclophosphamide treatment before intraportal readministration of an adenoviral vector can induce re-expression of the original gene construct in rat liver. Gene Ther. 6, 749–757 (1999).

    CAS  PubMed  Google Scholar 

  110. Smith, T. A., White, B. D., Gardner, J. M., Kaleko, M. & McClelland, A. Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector. Gene Ther. 3, 496–502 (1996).

    CAS  PubMed  Google Scholar 

  111. Endo, T. et al. In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer. Cancer Gene Ther. 9, 142–148 (2002).

    CAS  PubMed  Google Scholar 

  112. Toda, M., Iizuka, Y., Kawase, T., Uyemura, K. & Kawakami, Y. Immuno-viral therapy of brain tumors by combination of viral therapy with cancer vaccination using a replication-conditional HSV. Cancer Gene Ther. 9, 356–364 (2002).

    CAS  PubMed  Google Scholar 

  113. Hummel, J. L., Safroneeva, E. & Mossman K. L. The role of ICP0-null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma. Mol. Ther. 31 Aug 2005 (10.1016/j.ymthe.2005.07.533).

  114. Bergman, I. Re-targeting VSV: a candidate cancer therapeutic. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (12 Mar 2005).

  115. Breitbach, C. Investigation of the oncolytic activity of vesicular stomatitis virus in murine cancer models. Third International Meeting on Oncolytic Virus Therapeutics: Banff, Alberta (11 Mar 2005).

  116. Newcombe, N. G. et al. Cellular receptor interactions of C-cluster human group A coxsackieviruses. J. Gen. Virol. 84, 3041–3050 (2003).

    CAS  PubMed  Google Scholar 

  117. He, Y. et al. Complexes of poliovirus serotypes with their common cellular receptor, CD155. J. Virol. 77, 4827–4835 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Anderson, B. D., Nakamura, T., Russell, S. J. & Peng, K. W. High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus. Cancer Res. 64, 4919–4926 (2004).

    CAS  PubMed  Google Scholar 

  119. Lin, R., Noyce, R. S., Collins, S. E., Everett, R. D. & Mossman, K. L. The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes. J. Virol. 78, 1675–1684 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Norman, K. L., Hirasawa, K., Yang, A. D., Shields, M. A. & Lee, P. W. Reovirus oncolysis: the Ras–RalGEF–p38 pathway dictates host cell permissiveness to reovirus infection. Proc. Natl Acad. Sci. USA 101, 11099–11104 (2004).

    CAS  PubMed  Google Scholar 

  121. Stone, D. et al. Development and assessment of human adenovirus type 11 as a gene transfer vector. J. Virol. 79, 5090–5104 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Holterman, L. et al. Novel replication-incompetent vector derived from adenovirus type 11 (Ad11) for vaccination and gene therapy: low seroprevalence and non-cross-reactivity with Ad5. J. Virol. 78, 13207–13215 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Fukuhara, H. et al. Improvement of transduction efficiency of recombinant adenovirus vector conjugated with cationic liposome for human oral squamous cell carcinoma cell lines. Oral Oncol. 39, 601–609 (2003).

    CAS  PubMed  Google Scholar 

  124. Eto, Y. et al. PEGylated adenovirus vectors containing RGD peptides on the tip of PEG show high transduction efficiency and antibody evasion ability. J. Gene Med. 7, 604–612 (2005).

    CAS  PubMed  Google Scholar 

  125. Croyle, M. A., Chirmule, N., Zhang, Y. & Wilson, J. M. “Stealth” adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J. Virol. 75, 4792–4801 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Sailaja, G., HogenEsch, H., North, A., Hays, J. & Mittal, S. K. Encapsulation of recombinant adenovirus into alginate microspheres circumvents vector-specific immune response. Gene Ther. 9, 1722–1729 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Wakimoto, H., Fulci, G., Tyminski, E. & Chiocca, E. A. Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide's enhancement of viral oncolysis. Gene Ther. 11, 214–23 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Lu, W. et al. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers: a pilot phase II clinical trial. World J. Gastroenterol. 10, 3634–3638 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Myers, R. et al. Oncolytic activities of approved mumps and measles vaccines for therapy of ovarian cancer. Cancer Gene Ther. 12, 593–599 (2005).

    CAS  PubMed  Google Scholar 

  130. Sypula, J., Wang, F., Ma, Y., Bell, J. & McFadden, G. Myxoma virus tropism in human tumor cells. Gene Ther. Mol. Biol. 8, 103–114 (2004). First description of myxoma virus as an oncolytic agent.

    Google Scholar 

  131. Bergman, I., Whitaker-Dowling, P., Gao, Y. & Griffin, J. A. Preferential targeting of vesicular stomatitis virus to breast cancer cells. Virology 330, 24–33 (2004).

    CAS  PubMed  Google Scholar 

  132. Kamizono, J. et al. Survivin-responsive conditionally replicating adenovirus exhibits cancer-specific and efficient viral replication. Cancer Res. 65, 5284–5291 (2005).

    CAS  PubMed  Google Scholar 

  133. Rein, D. T. et al. A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer. Clin. Cancer Res. 11, 1327–1335 (2005).

    CAS  PubMed  Google Scholar 

  134. Kanerva, A. et al. A cyclooxygenase-2 promoter-based conditionally replicating adenovirus with enhanced infectivity for treatment of ovarian adenocarcinoma. Gene Ther. 11, 552–559 (2004).

    CAS  PubMed  Google Scholar 

  135. Mastrangeli, A. et al. “Sero-switch” adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. Hum. Gene Ther. 7, 79–87 (1996).

    CAS  PubMed  Google Scholar 

  136. Chung, R. Y., Saeki, Y. & Chiocca, E. A. B-myb promoter retargeting of herpes simplex virus γ34.5 gene-mediated virulence toward tumor and cycling cells. J. Virol. 73, 7556–7564 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Mastrangelo, M. J. et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther. 6, 409–422 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

J.B. and P.F. are supported by grants from CIHR, NCIC, and the Terry Fox Foundation.

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Correspondence to John C. Bell.

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DATABASES

Entrez Gene

CAR

CD46

EIF2α

MMP2

p53

PKR

RAS

SLAM

Entrez Genome

adenovirus type 5

measles virus

myxoma virus

Newcastle-disease virus

vaccinia virus

vesicular stomatitis virus

FURTHER INFORMATION

Adenovirus clinical trial

Reovirus clinical trial

Biovex herpes simplex virus clinical trial

Crusade laboratories herpes simplex virus clinical trial

Medigene herpes simplex virus clinical trials

Newcastle-disease virus clinical trial

Vaccinia virus information

Coxsackie virus information

Glossary

ENVELOPED AND NON-ENVELOPED VIRUSES

Broadly speaking, viruses can be subdivided into two groups: those that acquire a plasma membrane-derived envelope as they bud from an infected cell; or those that have only a protein coat and do not bud from the plasma membrane, but rather escape the infected cell following plasma membrane rupture.

IMMUNOLOGICAL MEMORY

The maintenance of an expanded number of circulating antigen-specific T- and B-lymphocytes, such that subsequent encounters with the same antigen are met with a more rapid immunological response.

ADJUVANT

Any compound that, when given simultaneously with antigen, increases the immunogenicity of that antigen, increasing the immune response.

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Parato, K., Senger, D., Forsyth, P. et al. Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 5, 965–976 (2005). https://doi.org/10.1038/nrc1750

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