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Oncolytic viruses

Nature Reviews Cancer volume 2, pages 938–950 (2002)Cite this article

Key Points

  • Viruses can be engineered to selectively infect and/or replicate in cancer cells.

  • Selective infection uses redirection of viral binding away from normal and towards normal cells.

  • Selective replication can be targeted towards cells with overactive RAS or defective interferon signalling, cells with defects in the p16/RB tumour-suppressor pathway, or cells with defects in the p53 tumour-suppressor pathway. Additional means of targeted replication use tumour-selective promoters to drive expression of viral genes.

  • Clinical trials have shown that oncolytic viruses — that are derived from adenoviruses such as herpes simplex virus and Newcastle disease virus — are well tolerated in humans.

  • The main goals of oncolytic viral research are to increase tumour selectivity by modifying the viral genome, to combine oncolytic viral therapy with standard radiation and chemotherapy, and to 'arm' the viruses with suicide cDNAs and/or cytokine cDNAs for multimodal treatment.

  • Improving our understanding of the mechanisms of viral oncolysis and the immune responses that virues induce, as well as improving the ability to image these viruses in vivo, should make this therapeutic approach safer and more effective.

Abstract

Although the cytotoxic effects of viruses are usually viewed in terms of pathogenicity, it is possible to harness this activity for therapeutic purposes. Viral genomes are highly versatile, and can be modified to direct their cytotoxicity towards cancer cells. These viruses are known as oncolytic viruses. How are viruses engineered to become tumour specific, and can they be used to safely treat cancer in humans?

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Figure 1: Oncolytic virus targeting of the p53 tumour suppressor pathway.
Figure 2: The RAS, IFN and double-stranded RNA-dependent protein kinase (PKR) pathways.
Figure 3: Targeting of oncolytic viruses to cells with defects in the p16/RB pathway.

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References

  1. 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). The first demonstration that a genetically engineered virus could be used for cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  2. Markert, J. M., Malick, A., Coen, D. M. & Martuza, R. L. Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir. Neurosurgery 32, 597–603 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Asada, T. Treatment of human cancer with mumps virus. Cancer 34, 1907–1928 (1974).

    Article  CAS  PubMed  Google Scholar 

  4. Wheelock, E. F. & Dingle, J. H. Observations on the repeated administration of viruses to a patient with acute leukemia. N. Engl. J. Med. 271, 645–651 (1964).

    Article  CAS  PubMed  Google Scholar 

  5. 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). A clinical trial of oncolytic virus with relatively encouraging results of efficacy.

    Article  CAS  PubMed  Google Scholar 

  6. Deweese, T. L. et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res. 61, 7464–7472 (2001).

    CAS  PubMed  Google Scholar 

  7. Rampling, R. et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP34. 5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther. 7, 859–866 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. 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). Shows that intracerebral injection of a mutant HSV11 was well tolerated in humans.

    Article  CAS  PubMed  Google Scholar 

  9. 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). Shows that systemic, intravenous administration of an OV was well tolerated in humans.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Wickham, T. J., Mathias, P., Cheresh, D. A. & Nemerow, G. R. Integrins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachment. Cell 73, 309–319 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Li, Y. et al. Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res. 59, 325–330 (1999).

    CAS  PubMed  Google Scholar 

  13. Hemmi, S., Geertsen, R., Mezzacasa, A., Peter, I. & Dummer, R. The presence of human coxsackievirus and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures. Hum. Gene Ther. 9, 2363–2373 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Geraghty, R. J., Krummenacher, C., Cohen, G. H., Eisenberg, R. J. & Spear, P. G. Entry of alpha herpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor. Science 280, 1618–1620 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Terry-Allison, T. et al. HVEA (herpesvirus entry mediator A), a coreceptor for herpes simplex virus entry, also participates in virus-induced cell fusion. J. Virol. 72, 5802–5810 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shukla, D. & Spear, P. G. Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. J. Clin. Invest. 108, 503–510 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yew, P. R. & Berk, A. J. Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. Nature 357, 82–85 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Bischoff, J. R. et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274, 373–376 (1996). Although this provided the first indication that viral mutant replication could be linked to a defect in a tumour-suppressor pathway, other studies (references 23–25) were not confirmatory. Therefore, the mechanism of ONYX-015 tumour selectivity remains controversial.

    Article  CAS  PubMed  Google Scholar 

  19. Ries, S. J. et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015). Nature Med. 6, 1128–1133 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Yang, C. T. et al. p14(arf) modulates the cytolytic effect of onyx-015 in mesothelioma cells with wild-type p53. Cancer Res. 61, 5959–5963 (2001).

    CAS  PubMed  Google Scholar 

  21. McCormick, F. ONXY-015 selectivity and the p14ARF pathway. Oncogene 19, 6670–6672 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. McCormick, F. Cancer therapy based on p53. Cancer J. Sci. Am. 5, 139–144 (1999).

    CAS  PubMed  Google Scholar 

  23. Hall, A. R., Dix, B. R., O'Carroll, S. J. & Braithwaite, A. W. p53-dependent cell death/apoptosis is required for a productive adenovirus infection. Nature Med. 4, 1068–1072 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Dix, B. R., O'Carroll, S. J., Myers, C. J., Edwards, S. J. & Baithwaite, A. W. Efficient induction of cell death by adenoviruses requires binding of E1B and p53. Cancer Res. 60, 2666–2672 (2000).

    CAS  PubMed  Google Scholar 

  25. Goodrum, F. D. & Ornelles, D. A. p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. J. Virol. 72, 9479–9490 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Leppard, K. N. & Shenk, T. The adenovirus E1B 55 kd protein influences mrna transport via an intranuclear effect on rna metabolism. EMBO J. 8, 2329–2336 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Harada, J. N. & Berk, A. J. p53-independent and -dependent requirements for E1B-55k in adenovirus type 5 replication. J. Virol. 73, 5333–5344 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Deleted in proof.

  29. Ramachandra, M. et al. Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy. Nature Biotechnol. 19, 1035–1041 (2001). Shows that alterations to viral genomes, such as eliminating redundant effects of viral gene products on cellular factors, led to more efficient and more selective oncolytic replication.

    Article  CAS  Google Scholar 

  30. Lill, N. L., Grossman, S. R., Ginsberg, D., Decaprio, J. & Livingston, D. M. Binding and modulation of p53 by p300/CBP coactivators. Nature 387, 823–827 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Sarnow, P. et al. Adenovirus early region 1B 58,000-dalton tumor antigen is physically associated with an early region 4 25,000-dalton protein in productively infected cells. J. Virol. 49, 692–700 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tollefson, A. E. et al. The adenovirus death protein (E3-11. 6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. J. Virol. 70, 2296–2306 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Raj, K., Ogston, P. & Beard, P. Virus-mediated killing of cells that lack p53 activity. Nature 412, 914–917 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Williams, B. R. PKR; a sentinel kinase for cellular stress. Oncogene 18, 6112–6120 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Deb, A., Haque, S. J., Mogensen, T., Silverman, R. H. & Williams, B. R. G. RNA-dependent protein kinase PKR is required for activation of NF-κB by IFN-γ in a STAT1-independent pathway. J. Immunol. 166, 6170–6180 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Mundschau, L. J. & Faller, D. V. Platelet-derived growth factor signal transduction through the interferon-inducible kinase PKR. Immediate early gene induction. J. Biol. Chem. 270, 3100–3106 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Coffey, M. C., Strong, J. E., Forsyth, P. A. & Lee, P. W. Reovirus therapy of tumors with activated Ras pathway. Science 282, 1332–1334 (1998). Links Ras overactivity with reovirus replication.

    Article  CAS  PubMed  Google Scholar 

  39. Lorence, R. M. et al. Complete regression of human neuroblastoma xenografts in athymic mice after local newcastle disease virus therapy. J. Natl Cancer Inst. 86, 1228–1233 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Heyman, M. et al. Interferon system defects in malignant T-cells. Leukemia 8, 425–434 (1994).

    CAS  PubMed  Google Scholar 

  41. Xu, B., Grander, D., Sangfelt, O. & Einhorn, S. Primary leukemia cells resistant to α-interferon in vitro are defective in the activation of the DNA-binding factor interferon-stimulated gene factor 3. Blood 84, 1942–1949 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Wong, L. H. et al. Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2 and p48-ISGF3γ. J. Biol. Chem. 272, 28779–28785 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Leib, D. A., Machalek, M. A., Williams, B. R., Silverman, R. H. & Virgin, H. W. Specific phenotypic restoration of an attenuated virus by knockout of a host resistance gene. Proc. Natl Acad. Sci. USA 97, 6097–6101 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stojdl, D. F. et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nature Med. 6, 821–825 (2000). Associated defects in interferon signalling with vesciculostomatitis virus replication.

    Article  CAS  PubMed  Google Scholar 

  45. Degregori, J., Kowalik, T. & Nevins, J. R. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes. Mol. Cell. Biol. 15, 4215–4224 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Whyte, P., Ruley, H. E. & Harlow, E. Two regions of the adenovirus early region 1A proteins are required for transformation. J. Virol. 62, 257–265 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fueyo, J. et al. A mutant oncolytic adenovirus targeting the RB pathway produces anti-glioma effect in vivo. Oncogene 19, 2–12 (2000). Showed that E1A–CR2 adenoviral mutant targets cells with PRB pathway defects.

    Article  CAS  PubMed  Google Scholar 

  48. Heise, C. et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nature Med. 6, 1134–1139 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Balague, C., Noya, F., Alemany, R., Chow, L. T. & Curiel, D. T. Human papillomavirus E6E7-mediated adenovirus cell killing: selectivity of mutant adenovirus replication in organotypic cultures of human keratinocytes. J. Virol. 75, 7602–7611 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Johnson, L. et al. Selectively replicating adenoviruses targeting deregulated E2F activity are potent, systemic antitumor agents. Cancer Cell 1, 325–337 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Goldstein, D. J. & Wller, S. K. Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant. Virology 166, 41–51 (1988).

    Article  CAS  PubMed  Google Scholar 

  52. Boviatsis, E. J. et al. Antitumor activity and reporter gene transfer into rat brain neoplasms inoculated with herpes simplex virus vectors defective in thymidine kinase or ribonucleotide reductase. Gene Ther. 1, 323–331 (1994).

    CAS  PubMed  Google Scholar 

  53. Carroll, N. M., Chiocca, E. A., Takahashi, K. & Tanabe, K. K. Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus. Ann. Surg. 224, 323–329; discussion 329–330 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chase, M., Chung, R. Y. & Chiocca, E. A. An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy. Nature Biotechnol. 16, 444–448 (1998).

    Article  CAS  Google Scholar 

  55. Elledge, S. J., Zhou, Z. & Allen, J. B. Ribonucleotide reductase: regulation, regulation, regulation. Trends Biochem. Sci. 17, 119–123 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Yoon, S. S. et al. An oncolytic herpes simplex virus type 1 selectively destroys diffuse liver metastases from colon carcinoma. FASEB J. 14, 301–311 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. 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). Shows that E2F-regulated promoters could be used to drive mutant HSV11 replication.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nakamura, H. et al. Regulation of herpes simplex virus γ(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5. J. Clin. Invest. 109, 871–882 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Puhlmann, M., Gnant, M., Brown, C. K., Alexander, H. R. & Bartlett, D. L. Thymidine kinase-deleted vaccinia virus expressing purine nucleoside phosphorylase as a vector for tumor-directed gene therapy. Hum. Gene Ther. 10, 649–657 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. Li, Y. et al. A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin. Cancer Res. 61, 6428–6436 (2001).

    CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nevins, J. R. Mechanism of activation of early viral transcription by the adenovirus E1A gene product. Cell 26, 213–220 (1981).

    Article  CAS  PubMed  Google Scholar 

  64. Steinwaerder, D. S., Carlson, C. A. & Lieber, A. DNA replication of first-generation adenovirus vectors in tumor cells. Hum. Gene Ther. 11, 1933–1948 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Steinwaerder, D. S. et al. Tumor-specific gene expression in hepatic metastases by a replication-activated adenovirus vector. Nature Med. 7, 240–243 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Grote, D. et al. Live attenuated measles virus induces regression of human lymphoma xenografts in immunodeficient mice. Blood 97, 3746–3754 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Bluming, A. Z. & Ziegler, J. L. Regression of Burkitt's lymphoma in association with measles infection. Lancet 105–107 (1971).

  68. Andreansky, S. et al. Evaluation of genetically engineered herpes simplex viruses as oncolytic agents for human malignant brain tumors. Cancer Res. 57, 1502–1509 (1997).

    CAS  PubMed  Google Scholar 

  69. Barth, R. F. Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J. Neurooncol. 36, 91–102 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Hunter, W. D. et al. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates. J. Virol. 73, 6319–6326 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kirn, D. Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned? Gene Ther. 8, 89–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. 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). Shows that multiple deletions in HSV11 increase its safety.

    Article  CAS  PubMed  Google Scholar 

  73. Kesari, S. et al. Therapy of experimental human brain tumors using a neuroattenuated herpes simplex virus mutant. Lab. Invest. 73, 636–648 (1995).

    CAS  PubMed  Google Scholar 

  74. Papanastassiou, V. et al. The potential for efficacy of the modified (ICP 34. 5(–)) herpes simplex virus HSV11716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther. 9, 398–406 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Baars, J. W. et al. Phase II study of interferon-γ and interleukin-2: tachyphylaxis of toxicity to the liver during increasing immune enhancement. J. Natl Cancer Inst. 85, 410–411 (1993).

    Article  CAS  PubMed  Google Scholar 

  76. Takahashi, N., Brouckaert, P. & Fiers, W. Induction of tolerance allows separation of lethal and antitumor activities of tumor necrosis factor in mice. Cancer Res. 51, 2366–2372 (1991).

    CAS  PubMed  Google Scholar 

  77. 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). Describes the limiting effect of hyperacute and acute immune responses on systemically administered viral oncolysis.

    Article  CAS  PubMed  Google Scholar 

  78. Ikeda, K. et al. Complement depletion facilitates the infection of multiple brain tumors by an intravascular, replication-conditional herpes simplex virus mutant. J. Virol. 74, 4765–4775 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wakimoto, H. et al. The complement response against an oncolytic virus is species-specific in its activation pathways. Mol. Ther. 5, 275–282 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Petrowsky, H. et al. Functional interaction between fluorodeoxyuridine-induced cellular alterations and replication of a ribonucleotide reductase-negative herpes simplex virus. J. Virol. 75, 7050–7058 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Toyoizumi, T. et al. Combined therapy with chemotherapeutic agents and herpes simplex virus type 1 ICP34.5 mutant (HSV1-1716) in human non-small cell lung cancer. Hum. Gene Ther. 10, 3013–3029 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Advani, S. J. et al. Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors. Gene Ther. 5, 160–165 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Chung, S. M. et al. The use of a genetically engineered herpes simplex virus (R7020) with ionizing radiation for experimental hepatoma. Gene Ther. 9, 75–80 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Blank, S. V. et al. Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation. Hum. Gene Ther. 13, 627–639 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Spear, M. A. et al. Cytotoxicity, apoptosis, and viral replication in tumor cells treated with oncolytic ribonucleotide reductase-defective herpes simplex type 1 virus (hrR3) combined with ionizing radiation. Cancer Gene Ther. 7, 1051–1059 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Jorgensen, T. J. et al. Ionizing radiation does not alter the antitumor activity of herpes simplex virus vector G207 in subcutaneous tumor models of human and murine prostate cancer. Neoplasia 3, 451–456 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Freytag, S. O., Rogulski, K. R., Paielli, D. L., Gilbert, J. D. & Kim, J. H. A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum. Gene Ther. 9, 1323–1333 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Harsh, G. R. et al. Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study. J. Neurosurg. 92, 804–811 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Ichikawa, T. & Chiocca, E. A. Comparative analyses of transgene delivery and expression in tumors inoculated with a replication-conditional or -defective viral vector. Cancer Res. 61, 5336–5339 (2001).

    CAS  PubMed  Google Scholar 

  91. Boviatsis, E. J. et al. Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Res. 54, 5745–5751 (1994). First demonstration that viral oncolysis could be combined with viral-mediated activation of a prodrug (gene therapy).

    CAS  PubMed  Google Scholar 

  92. Kramm, C. M. et al. Long-term survival in a rodent model of disseminated brain tumors by combined intrathecal delivery of herpes vectors and ganciclovir treatment. Hum. Gene Ther. 7, 1989–1994 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Kasuya, H. et al. Intraperitoneal delivery of hrR3 and ganciclovir prolongs survival in mice with disseminated pancreatic cancer. J. Surg. Oncol. 72, 136–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Samoto, K. et al. A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice. Neurosurgery 50, 599–605; discussion 605–606 (2002).

    PubMed  Google Scholar 

  95. Carroll, N. M., Chase, M., Chiocca, E. A. & Tanabe, K. K. The effect of ganciclovir on herpes simplex virus-mediated oncolysis. J. Surg. Res. 69, 413–417 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Kramm, C. M. et al. Therapeutic efficiency and safety of a second-generation replication-conditional HSV11 vector for brain tumor gene therapy. Hum. Gene Ther. 8, 2057–2068 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Morris, J. C. & Wildner, O. Therapy of head and neck squamous cell carcinoma with an oncolytic adenovirus expressing HSV1-tk. Mol. Ther. 1, 56–62 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Todo, T., Rabkin, S. D. & Martuza, R. L. Evaluation of ganciclovir-mediated enhancement of the antitumoral effect in oncolytic, multimutated herpes simplex virus type 1 (G207) therapy of brain tumors. Cancer Gene Ther. 7, 939–946 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Wildner, O., Blaese, R. M. & Morris, J. C. Synergy between the herpes simplex virus tk/ganciclovir prodrug suicide system and the topoisomerase I inhibitor topotecan. Hum. Gene Ther. 10, 2679–2687 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Yoon, S. S., Carroll, N. M., Chiocca, E. A. & Tanabe, K. K. Cancer gene therapy using a replication-competent herpes simplex virus type 1 vector. Ann. Surg. 228, 366–374 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Aghi, M., Chou, T. C., Suling, K., Breakefield, X. O. & Chiocca, E. A. Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganciclovir/herpes simplex virus thymidine kinase gene therapies. Cancer Res. 59, 3861–3865 (1999).

    CAS  PubMed  Google Scholar 

  102. Clarke, L. & Waxman, D. J. Oxidative metabolism of cyclophosphamide: identification of the hepatic monooxygenase catalysts of drug activation. Cancer Res. 49, 2344–2350 (1989).

    CAS  PubMed  Google Scholar 

  103. Maccubbin, A. E., Caballes, L., Riordan, J. M., Huang, D. H. & Gurtoo, H. L. A cyclophosphamide/DNA phosphoester adduct formed in vitro and in vivo. Cancer Res. 51, 886–892 (1991).

    CAS  PubMed  Google Scholar 

  104. Nakamura, H. et al. Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil. Cancer Res. 61, 5447–5452 (2001).

    CAS  PubMed  Google Scholar 

  105. Andreansky, S. et al. Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins. Gene Ther. 5, 121–130 (1998). Demonstrates how cytokine cDNAs could be delivered by an oncolytic virus.

    Article  CAS  PubMed  Google Scholar 

  106. Parker, J. N. et al. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc. Natl Acad. Sci. USA 97, 2208–2213 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Todo, T., Martuza, R. L., Dallman, M. J. & Rabkin, S. D. In situ expression of soluble B7-1 in the context of oncolytic herpes simplex virus induces potent antitumor immunity. Cancer Res. 61, 153–161 (2001).

    CAS  PubMed  Google Scholar 

  108. Toda, M., Martuza, R. L., Kojima, H. & Rabkin, S. D. In situ cancer vaccination: an IL-12 defective vector/replication-competent herpes simplex virus combination induces local and systemic antitumor activity. J. Immunol. 160, 4457–4464 (1998).

    CAS  PubMed  Google Scholar 

  109. Ichikawa, T. et al. Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconversion by a replicating oncolytic viral vector. Cancer Res. 61, 864–868 (2001).

    CAS  PubMed  Google Scholar 

  110. Aghi, M., Kramm, C. M., Chou, T. C., Breakefield, X. O. & Chiocca, E. A. Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies. J. Natl Cancer Inst. 90, 370–380 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Todo, T. et al. Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus. Hum. Gene Ther. 10, 2741–2755 (1999). Shows how increased antitumour immunity can be increased by viral oncolysis.

    Article  CAS  PubMed  Google Scholar 

  112. Chen, Y., Yu, D. C., Charlton, D. & Henderson, D. R. Pre-existent adenovirus antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model: implications and proposals for human therapy. Hum. Gene Ther. 11, 1553–1567 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Todo, T., Martuza, R. L., Rabkin, S. D. & Johnson, P. A. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc. Natl Acad. Sci. USA 98, 6396–6401 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Schellingerhout, D., Rainov, N. G., Breakefield, X. O. & Weissleder, R. Quantitation of HSV1 mass distribution in a rodent brain tumor model. Gene Ther. 7, 1648–1655 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Jacobs, A. et al. Positron emission tomography-based imaging of transgene expression mediated by replication-conditional, oncolytic herpes simplex virus type 1 mutant vectors in vivo. Cancer Res. 61, 2983–2995 (2001).

    CAS  PubMed  Google Scholar 

  116. Contag, P. R., Olomu, I. N., Stevenson, D. K. & Contag, C. H. Bioluminescent indicators in living mammals. Nature Med. 4, 245–247 (1998).

    Article  CAS  PubMed  Google Scholar 

  117. Peng, K. W., Facteau, S., Wegman, T., O'Kane, D. & Russell, S. J. Non-invasive in vivo monitoring of trackable viruses expressing soluble marker peptides. Nature Med. 8, 527–531 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Coukos, G. et al. Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer. Clin. Cancer Res. 5, 1523–1537 (1999).

    CAS  PubMed  Google Scholar 

  119. Herrlinger, U. et al. Neural precursor cells for delivery of replication-conditional HSV1-1 vectors to intracerebral gliomas. Mol. Ther. 1, 347–357 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. He, B. et al. Suppression of the phenotype of γ(1)34.5-herpes simplex virus 1: failure of activated RNA-dependent protein kinase to shut off protein synthesis is associated with a deletion in the domain of the α47 gene. J. Virol. 71, 6049–6054 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mohr, I. et al. A herpes simplex virus type 1 γ34.5 second-site suppressor mutant that exhibits enhanced growth in cultured glioblastoma cells is severely attenuated in animals. J. Virol. 75, 5189–5196 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Yew, P. R., Kao, C. C. & Berk, A. J. Dissection of functional domains in the adenovirus 2 early 1B 55K polypeptide by suppressor-linker insertional mutagenesis. Virology 179, 795–805 (1990).

    Article  CAS  PubMed  Google Scholar 

  123. Chakravarti, D. et al. A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity. Cell 96, 393–403 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. He, B., Gross, M. & Roizman, B. The γ(1)34.5 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Strong, J. E., Coffey, M. C., Tang, D., Sabinin, P. & Lee, P. W. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 17, 3351–3362 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wilcox, M. E. et al. Reovirus as an oncolytic agent against experimental human malignant gliomas. J. Natl Cancer Inst. 93, 903–912 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Norman, K. L. et al. Reovirus oncolysis of human breast cancer. Hum. Gene Ther. 13, 641–652 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Kitajewski, J. et al. Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced EIF-2 α kinase. Cell 45, 195–200 (1986).

    Article  CAS  PubMed  Google Scholar 

  129. Vuyisich, M., Spanggord, R. J. & Beal, P. A. The binding site of the RNA-dependent protein kinase (PKR) on EBER1 RNA from Epstein–Barr virus. EMBO Rep. 3, 622–627 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Taylor, D. R., Shi, S. T., Romano, P. R., Barber, G. N. & Lai, M. M. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285, 107–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Cai, R., Carpick, B., Chun, R. F., Jeang, K. T. & Williams, B. R. HIV-I TAT inhibits PKR activity by both RNA-dependent and RNA-independent mechanisms. Arch. Biochem. Biophys. 373, 361–367 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Davies, M. V., Chang, H. W., Jacobs, B. L. & Kaufman, R. J. The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-dependent protein kinase by different mechanisms. J. Virol. 67, 1688–1692 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lu, Y., Wambach, M., Katze, M. G. & Krug, R. M. Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the ElF-2 translation initiation factor. Virology 214, 222–228 (1995).

    Article  CAS  PubMed  Google Scholar 

  134. Bergmann, M. et al. A genetically engineered influenza A virus with ras-dependent oncolytic properties. Cancer Res 61, 8188–8193 (2001).

    CAS  PubMed  Google Scholar 

  135. Lorence, R. M. et al. Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res. 54, 6017–6021 (1994).

    CAS  PubMed  Google Scholar 

  136. Boviatsis, E. J. et al. Gene transfer into experimental brain tumors mediated by adenovirus, herpes simplex virus, and retrovirus vectors. Hum. Gene Ther. 5, 183–191 (1994).

    Article  CAS  PubMed  Google Scholar 

  137. Pawlik, T. M. et al. Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene. Cancer 95, 1171–1181 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Hemminki, A. et al. Targeting oncolytic adenoviral agents to the epidermal growth factor pathway with a secretory fusion molecule. Cancer Res. 61, 6377–6381 (2001).

    CAS  PubMed  Google Scholar 

  139. Suzuki, K. et al. A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. Clin. Cancer Res. 7, 120–126 (2001). Describes how adenoviral infection could be retargeted away from CAR.

    CAS  PubMed  Google Scholar 

  140. van der Poel, H. G. et al. Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer. J. Urol. 168, 266–272 (2002).

    Article  Google Scholar 

  141. Shayakhmetov, D. M., Li, Z. Y., Ni, S. & Lieber, A. Targeting of adenovirus vectors to tumor cells does not enable efficient transduction of breast cancer metastases. Cancer Res. 62, 1063–1068 (2002).

    CAS  PubMed  Google Scholar 

  142. Rodriguez, R. et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res. 57, 2559–2563 (1997).

    CAS  PubMed  Google Scholar 

  143. 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).

    CAS  PubMed  Google Scholar 

  144. Chen, Y. et al. CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Res. 61, 5453–5460 (2001).

    CAS  PubMed  Google Scholar 

  145. Zhang, J. et al. Identification of human uroplakin II promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. Cancer Res. 62, 3743–3750 (2002).

    CAS  PubMed  Google Scholar 

  146. Doronin, K. et al. Tissue-specific, tumor-selective, replication-competent adenovirus vector for cancer gene therapy. J. Virol. 75, 3314–3324 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mullen, J. T. et al. Regulation of herpes simplex virus 1 replication using tumor-associated promoters. Ann. Surg. (in the press).

  148. Miyatake, S. I. et al. Hepatoma-specific antitumor activity of an albumin enhancer/promoter regulated herpes simplex virus in vivo. Gene Ther. 6, 564–572 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Fu, X. & Zhang, X. Potent systemic antitumor activity from an oncolytic herpes simplex virus of syncytial phenotype. Cancer Res. 62, 2306–2312 (2002).

    CAS  PubMed  Google Scholar 

  150. Zhang, J. F. et al. Treatment of a human breast cancer xenograft with an adenovirus vector containing an interferon gene results in rapid regression due to viral oncolysis and gene therapy. Proc. Natl Acad. Sci. USA 93, 4513–4518 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wildner, O., Blaese, R. M. & Morris, J. C. Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of herpes simplex virus-thymidine kinase. Cancer Res. 59, 410–413 (1999).

    CAS  PubMed  Google Scholar 

  152. Nanda, D. et al. Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. Cancer Res. 61, 8743–8750 (2001).

    CAS  PubMed  Google Scholar 

  153. Zager, J. S. et al. Combination vascular delivery of herpes simplex oncolytic viruses and amplicon mediated cytokine gene transfer is effective therapy for experimental liver cancer. Mol. Med. 7, 561–568 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Wong, R. J. et al. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. Hum. Gene Ther. 12, 253–265 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. McCart, J. A. et al. Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression. Gene Ther. 7, 1217–1223 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Pechan, P. A. et al. A novel 'piggyback' packaging system for herpes simplex virus amplicon vectors. Hum. Gene Ther. 7, 2003–2013 (1996).

    Article  CAS  PubMed  Google Scholar 

  157. Meignier, B., Longnecker, R. & Roizman, B. In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020: construction and evaluation in rodents. J. Infect. Dis. 158, 602–614 (1988).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author would like to dedicate this review to the memory of K. Ikeda (Massachusetts General Hospital and Keio University, Japan). The innumerable contributions from members of the Chiocca laboratory are recognized. Finally, D. Louis (Massachusetts General Hospital, Department of Neuropathology) is recognized for his critical reading of this review.

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Authors and Affiliations

  1. Molecular Neuro-Oncology Laboratories, Neurosurgery Service, Massachusetts General Hospital, East Building, 13th Street, Bldg 149, Charlestown, 02129, Massachusetts, USA

    E. Antonio Chiocca

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DATABASES

GenBank

E1A

E1B

E4

ICP34.5

ul39

LocusLink

AFP

B-Myb

CAR

CBP

E2F

EGFR

eiF2α

p300

p53

PKR

RAS

RB

FURTHER INFORMATION

Cancer clinical trials

Oncolytic Virus web page

Glossary

VIRAL TITRE

A quantitative measure of viral replication expressed as the total number of infectious units generated per ml of culture.

INTERNAL RIBOSOME ENTRY SITE

(IRES). A defined nucleic-acid sequence that enables attachment of the ribosomal protein synthetic machinery and translation of a downstream mRNA.

THERAPEUTIC INDEX

The ratio of dose of virus needed to obtain anti cancer effect versus dose of virus needed to obtain toxic effect against normal cells.

MULTIPLICITY OF INFECTION

The ratio of number of infectious units of oncolytic virus to number of cells.

DYSPNEA

Shortness of breath.

VIRAL YIELD

A quantitative measure of viral replication expressed as total number of infectious units generated.

BURST SIZE

A measure of viral replication expressed as infectious units generated per infected cell. For example, a burst size of 1,000 would indicate that 1,000 progeny viruses were generated per each initially infected cell.

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Antonio Chiocca, E. Oncolytic viruses. Nat Rev Cancer 2, 938–950 (2002). https://doi.org/10.1038/nrc948

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