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Replication-selective oncolytic viruses in the treatment of cancer

An Erratum to this article was published on 16 March 2005

Abstract

In the search for novel strategies, oncolytic virotherapy has recently emerged as a viable approach to specifically kill tumor cells. Unlike conventional gene therapy, it uses replication competent viruses that are able to spread through tumor tissue by virtue of viral replication and concomitant cell lysis. Recent advances in molecular biology have allowed the design of several genetically modified viruses, such as adenovirus and herpes simplex virus that specifically replicate in, and kill tumor cells. On the other hand, viruses with intrinsic oncolytic capacity are also being evaluated for therapeutic purposes. In this review, an overview is given of the general mechanisms and genetic modifications by which these viruses achieve tumor cell-specific replication and antitumor efficacy. However, although generally the oncolytic efficacy of these approaches has been demonstrated in preclinical studies the therapeutic efficacy in clinical trails is still not optimal. Therefore, strategies are evaluated that could further enhance the oncolytic potential of conditionally replicating viruses. In this respect, the use of tumor-selective viruses in conjunction with other standard therapies seems most promising. However, still several hurdles regarding clinical limitations and safety issues should be overcome before this mode of therapy can become of clinical relevance.

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References

  1. Everett H, McFadden G . Apoptosis: an innate immune response to virus infection. Trends Microbiol. 1999;7:160–165.

    Article  CAS  PubMed  Google Scholar 

  2. Madigan MT, Martinko JM, Parker J . Brock Biology of Microorganisms. 9th edn. Upper Saddal River, NJ: Prentice-Hall, Inc.; 2000.

    Google Scholar 

  3. de Pace N . Sulla scomparsa di un enorme cancro vegetante del collo dell’utero senza cura chirugica. Ginecologia. 1912;9:82–89.

    Google Scholar 

  4. Bluming AZ, Ziegler JL . Regression of Burkitt's lymphoma in association with measles infection. Lancet. 1971;2:105–106.

    Article  CAS  PubMed  Google Scholar 

  5. Taqi AM, Abdurrahman MB, Yakubu AM, Fleming AF . Regression of Hodgkin's disease after measles. Lancet. 1981;1:1112.

    Article  CAS  PubMed  Google Scholar 

  6. Huebner RJ, Rowe WP, Schatten WE, Smith RR, Thomas LB . Studies on the use of viruses in the treatment of carcinoma of the cervix. Cancer. 1956;9:1211–1218.

    Article  CAS  PubMed  Google Scholar 

  7. Southam CM . Present status of oncolytic virus studies. Trans NY Acad Sci. 1960;22:657–673.

    Article  CAS  Google Scholar 

  8. Asada T . Treatment of human cancer with mumps virus. Cancer. 1974;34:1907–1928.

    Article  CAS  PubMed  Google Scholar 

  9. Okuno Y, Asada T, Yamanishi K, et al. Studies on the use of mumps virus for treatment of human cancer. Biken J. 1978;21:37–49.

    CAS  PubMed  Google Scholar 

  10. Webb HE, Molomut N, Padnos M, Wetherley-Mein G . The treatment of 18 cases of malignant disease with an arenavirus. Clin Oncol. 1975;1:157–169.

    CAS  PubMed  Google Scholar 

  11. Webb HE, Wetherley-Mein G, Smith CE, McMahon D . Leukaemia and neoplastic processes treated with Langat and Kyasanur Forest disease viruses: a clinical and laboratory study of 28 patients. BMJ. 1966;5482:258–266.

    Article  Google Scholar 

  12. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM . Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science. 1991;252:854–856.

    Article  CAS  PubMed  Google Scholar 

  13. Hashiro G, Loh PC, Yau JT . The preferential cytotoxicity of reovirus for certain transformed cell lines. Arch Virol. 1977;54:307–315.

    Article  CAS  PubMed  Google Scholar 

  14. Coffey MC, Strong JE, Forsyth PA, Lee PW . Reovirus therapy of tumors with activated Ras pathway. Science. 1998;282:1332–1334.

    Article  CAS  PubMed  Google Scholar 

  15. Strong JE, Lee PW . The v-erbB oncogene confers enhanced cellular susceptibility to reovirus infection. J Virol. 1996;70:612–616.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Strong JE, Coffey MC, Tang D, Sabinin P, Lee PW . The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 1998;17:3351–3362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kinzler KW, Vogelstein B . Lessons from hereditary colorectal cancer. Cell. 1996;87:159–170.

    Article  CAS  PubMed  Google Scholar 

  18. Norman KL, Coffey MC, Hirasawa K, et al. Reovirus oncolysis of human breast cancer. Hum Gene Ther. 2002;13:641–652.

    Article  CAS  PubMed  Google Scholar 

  19. Alain T, Hirasawa K, Pon KJ, et al. Reovirus therapy of lymphoid malignancies. Blood. 2002;100:4146–4153.

    Article  CAS  PubMed  Google Scholar 

  20. Hirasawa K, Nishikawa SG, Norman KL, Alain T, Kossakowska A, Lee PW . Oncolytic reovirus against ovarian and colon cancer. Cancer Res. 2002;62:1696–1701.

    CAS  PubMed  Google Scholar 

  21. Thirukkumaran CM, Luider JM, Stewart DA, et al. Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation. Blood. 2003;102:377–387.

    Article  CAS  PubMed  Google Scholar 

  22. Hirasawa K, Nishikawa SG, Norman KL, et al. Systemic reovirus therapy of metastatic cancer in immune-competent mice. Cancer Res. 2003;63:348–353.

    CAS  PubMed  Google Scholar 

  23. Flanagan AD, Love R, Tesar W . Propagation of Newcastle disease virus in Ehrlich ascites cells in vitro and in vivo. Proc Soc Exp Biol Med. 1955;90:82–86.

    Article  CAS  PubMed  Google Scholar 

  24. Lorence RM, Katubig BB, Reichard KW, et al. Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res. 1994;54:6017–6021.

    CAS  PubMed  Google Scholar 

  25. Phuangsab A, Lorence RM, Reichard KW, Peeples ME, Walter RJ . Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett. 2001;172:27–36.

    Article  CAS  PubMed  Google Scholar 

  26. Sinkovics JG, Horvath JC . Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol. 2000;16:1–15.

    Article  CAS  PubMed  Google Scholar 

  27. Mullen JT, Tanabe KK . Viral oncolysis. Oncologist. 2002;7:106–119.

    Article  CAS  PubMed  Google Scholar 

  28. Pecora AL, Rizvi N, Cohen GI, et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol. 2002;20:2251–2266.

    Article  CAS  PubMed  Google Scholar 

  29. Stojdl DF, Lichty B, Knowles S, et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med. 2000;6:821–825.

    Article  CAS  PubMed  Google Scholar 

  30. Stojdl DF, Lichty BD, ten Oever BR, et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell. 2003;4:263–275.

    Article  CAS  PubMed  Google Scholar 

  31. Shinozaki K, Ebert O, Kournioti C, Tai YS, Woo SL . Oncolysis of multifocal hepatocellular carcinoma in the rat liver by hepatic artery infusion of vesicular stomatitis virus. Mol Ther. 2004;9:368–376.

    Article  CAS  PubMed  Google Scholar 

  32. Rommelaere J, Cornelis JJ . Antineoplastic activity of parvoviruses. J Virol Methods. 1991;33:233–251.

    Article  CAS  PubMed  Google Scholar 

  33. Herrero YC, Cornelis JJ, Herold-Mende C, Rommelaere J, Schlehofer JR, Geletneky K . Parvovirus H-1 infection of human glioma cells leads to complete viral replication and efficient cell killing. Int J Cancer. 2004;109:76–84.

    Article  CAS  Google Scholar 

  34. Cornelis JJ, Spruyt N, Spegelaere P, et al. Sensitization of transformed rat fibroblasts to killing by parvovirus minute virus of mice correlates with an increase in viral gene expression. J Virol. 1988;62:3438–3444.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Moehler M, Blechacz B, Weiskopf N, et al. Effective infection, apoptotic cell killing and gene transfer of human hepatoma cells but not primary hepatocytes by parvovirus H1 and derived vectors. Cancer Gene Ther. 2001;8:158–167.

    Article  CAS  PubMed  Google Scholar 

  36. Olijslagers S, Dege AY, Dinsart C, et al. Potentiation of a recombinant oncolytic parvovirus by expression of apoptin. Cancer Gene Ther. 2001;8:958–965.

    Article  CAS  PubMed  Google Scholar 

  37. Haag A, Menten P, Van Damme J, Dinsart C, Rommelaere J, Cornelis JJ . Highly efficient transduction and expression of cytokine genes in human tumor cells by means of autonomous parvovirus vectors; generation of antitumor responses in recipient mice. Hum Gene Ther. 2000;11:597–609.

    Article  CAS  PubMed  Google Scholar 

  38. Ring CJ . Cytolytic viruses as potential anti-cancer agents. J Gen Virol. 2002;83 (Part 3):491–502.

    Article  PubMed  Google Scholar 

  39. Galanis E, Vile R, Russell SJ . Delivery systems intended for in vivo gene therapy of cancer: targeting and replication competent viral vectors. Crit Rev Oncol Hematol. 2001;38:177–192.

    Article  CAS  PubMed  Google Scholar 

  40. Post DE, Khuri FR, Simons JW, Van Meir EG . Replicative oncolytic adenoviruses in multimodal cancer regimens. Hum Gene Ther. 2003;14:933–946.

    Article  CAS  PubMed  Google Scholar 

  41. Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996;274:373–376.

    Article  CAS  PubMed  Google Scholar 

  42. Rogulski KR, Freytag SO, Zhang K, et al. In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy. Cancer Res. 2000;60:1193–1196.

    CAS  PubMed  Google Scholar 

  43. Goodrum FD, Ornelles DA . p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. J Virol. 1998;72:9479–9490.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur HH . Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. J Virol. 1998;72:9470–9478.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Harada JN, Berk AJ . p53-Independent and -dependent requirements for E1B-55K in adenovirus type 5 replication. J Virol. 1999;73:5333–5344.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ries SJ, Brandts CH, Chung AS, et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015). Nat Med. 2000;6:1128–1133.

    Article  CAS  PubMed  Google Scholar 

  47. Dobner T, Horikoshi N, Rubenwolf S, Shenk T . Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor. Science. 1996;272:1470–1473.

    Article  CAS  PubMed  Google Scholar 

  48. Kirn D . Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials. Expert Opin Biol Ther. 2001;1:525–538.

    Article  CAS  PubMed  Google Scholar 

  49. Nemunaitis J, Khuri F, Ganly I, et al. Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol. 2001;19:289–298.

    Article  CAS  PubMed  Google Scholar 

  50. Nemunaitis J, Ganly I, Khuri F, et al. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. Cancer Res. 2000;60:6359–6366.

    CAS  PubMed  Google Scholar 

  51. Ganly I, Kirn D, Eckhardt G, et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res. 2000;6:798–806.

    CAS  PubMed  Google Scholar 

  52. Mulvihill S, Warren R, Venook A, et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Therapy. 2001;8:308–315.

    Article  CAS  PubMed  Google Scholar 

  53. Vasey PA, Shulman LN, Campos S, et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol. 2002;20:1562–1569.

    CAS  PubMed  Google Scholar 

  54. Habib NA, Sarraf CE, Mitry RR, et al. E1B-deleted adenovirus (dl1520) gene therapy for patients with primary and secondary liver tumors. Hum Gene Ther. 2001;12:219–226.

    Article  CAS  PubMed  Google Scholar 

  55. Reid T, Galanis E, Abbruzzese J, 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 Therapy. 2001;8:1618–1626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Reid T, Galanis E, Abbruzzese J, et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res. 2002;62:6070–6079.

    CAS  PubMed  Google Scholar 

  57. Nemunaitis J, Cunningham C, Buchanan A, et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Therapy. 2001;8:746–759.

    Article  CAS  PubMed  Google Scholar 

  58. Hamid O, Varterasian ML, Wadler S, et al. Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:1498–1504.

    Article  CAS  PubMed  Google Scholar 

  59. Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med. 2000;6:1134–1139.

    Article  CAS  PubMed  Google Scholar 

  60. Fueyo J, Gomez-Manzano C, Alemany R, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene. 2000;19:2–12.

    Article  CAS  PubMed  Google Scholar 

  61. Gomez-Manzano C, Balague C, Alemany R, et al. A novel E1A-E1B mutant adenovirus induces glioma regression in vivo. Oncogene. 2004;23:1821–1828.

    Article  CAS  PubMed  Google Scholar 

  62. Cascallo M, Capella G, Mazo A, Alemany R . Ras-dependent oncolysis with an adenovirus VAI mutant. Cancer Res. 2003;63:5544–5550.

    CAS  PubMed  Google Scholar 

  63. Jia WW, McDermott M, Goldie J, Cynader M, Tan J, Tufaro F . Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1. J Natl Cancer Inst. 1994;86:1209–1215.

    Article  CAS  PubMed  Google Scholar 

  64. Boviatsis EJ, Scharf JM, Chase M, 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 Therapy. 1994;1:323–331.

    CAS  PubMed  Google Scholar 

  65. Whitley RJ, Kern ER, Chatterjee S, Chou J, Roizman B . Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models. J Clin Invest. 1993;91:2837–2843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bolovan CA, Sawtell NM, Thompson RL . ICP34.5 mutants of herpes simplex virus type 1 strain 17syn+ are attenuated for neurovirulence in mice and for replication in confluent primary mouse embryo cell cultures. J Virol. 1994;68:48–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mineta T, Rabkin SD, Martuza RL . Treatment of malignant gliomas using ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral mutant. Cancer Res. 1994;54:3963–3966.

    CAS  PubMed  Google Scholar 

  68. Carroll NM, Chiocca EA, Takahashi K, Tanabe KK . Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus. Ann Surg. 1996;224:323–329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL . Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med. 1995;1:938–943.

    Article  CAS  PubMed  Google Scholar 

  70. Varghese S, Rabkin SD . Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther. 2002;9:967–978.

    Article  CAS  PubMed  Google Scholar 

  71. Markert JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Therapy. 2000;7:867–874.

    Article  CAS  PubMed  Google Scholar 

  72. 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. 1988;158:602–614.

    Article  CAS  PubMed  Google Scholar 

  73. Cozzi PJ, Malhotra S, McAuliffe P, et al. Intravesical oncolytic viral therapy using attenuated, replication-competent herpes simplex viruses G207 and Nv1020 is effective in the treatment of bladder cancer in an orthotopic syngeneic model. FASEB J. 2001;15:1306–1308.

    Article  CAS  PubMed  Google Scholar 

  74. Bennett JJ, Delman KA, Burt BM, et al. Comparison of safety, delivery, and efficacy of two oncolytic herpes viruses (G207 and NV1020) for peritoneal cancer. Cancer Gene Ther. 2002;9:935–945.

    Article  CAS  PubMed  Google Scholar 

  75. Puhlmann M, Brown CK, Gnant M, et al. Vaccinia as a vector for tumor-directed gene therapy: biodistribution of a thymidine kinase-deleted mutant. Cancer Gene Ther. 2000;7:66–73.

    Article  CAS  PubMed  Google Scholar 

  76. McCart JA, Ward JM, Lee J, et al. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 2001;61:8751–8757.

    CAS  PubMed  Google Scholar 

  77. Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E . Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci USA. 2000;97:6803–6808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Muster T, Rajtarova J, Sachet M, et al. Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants. Int J Cancer. 2004;110:15–21.

    Article  CAS  PubMed  Google Scholar 

  79. Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res. 1997;57:2559–2563.

    CAS  PubMed  Google Scholar 

  80. Deweese TL, Vander Poel H, Li S, 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. 2001;61:7464–7472.

    CAS  PubMed  Google Scholar 

  81. Yu DC, Chen Y, Seng M, Dilley J, Henderson DR . The addition of adenovirus type 5 region E3 enables calydon virus 787 to eliminate distant prostate tumor xenografts. Cancer Res. 1999;59:4200–4203.

    CAS  PubMed  Google Scholar 

  82. Matsubara S, Wada Y, Gardner TA, et al. A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone stroma in an experimental model of androgen-independent prostate cancer bone metastasis. Cancer Res. 2001;61:6012–6019.

    CAS  PubMed  Google Scholar 

  83. Benjamin R, Helman L, Meyers P, Reaman G . A phase I/II dose escalation and activity study of intravenous injections of OCaP1 for subjects with refractory osteosarcoma metastatic to lung. Hum Gene Ther. 2001;12:1591–1593.

    CAS  PubMed  Google Scholar 

  84. Hallenbeck PL, Chang YN, Hay C, et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther. 1999;10:1721–1733.

    Article  CAS  PubMed  Google Scholar 

  85. Takahashi M, Sato T, Sagawa T, et al. E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor. Mol Ther. 2002;5 (5 Part 1):627–634.

    Article  CAS  PubMed  Google Scholar 

  86. Kurihara T, Brough DE, Kovesdi I, Kufe DW . Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen. J Clin Invest. 2000;106:763–771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nettelbeck DM, Rivera AA, Balague C, Alemany R, Curiel DT . Novel oncolytic adenoviruses targeted to melanoma: specific viral replication and cytolysis by expression of E1A mutants from the tyrosinase enhancer/promoter. Cancer Res. 2002;62:4663–4670.

    CAS  PubMed  Google Scholar 

  88. Banerjee NS, Rivera AA, Wang M, et al. Analyses of melanoma-targeted oncolytic adenoviruses with tyrosinase enhancer/promoter-driven E1A, E4, or both in submerged cells and organotypic cultures. Mol Cancer Ther. 2004;3:437–449.

    CAS  PubMed  Google Scholar 

  89. Barker SD, Dmitriev IP, Nettelbeck DM, et al. Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma. Gene Therapy. 2003;10:1198–1204.

    Article  CAS  PubMed  Google Scholar 

  90. Adachi Y, Reynolds PN, Yamamoto M, et al. A midkine promoter-based conditionally replicative adenovirus for treatment of pediatric solid tumors and bone marrow tumor purging. Cancer Res. 2001;61:7882–7888.

    CAS  PubMed  Google Scholar 

  91. Fuerer C, Iggo R . Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumor cells with constitutive activation of the wnt signalling pathway. Gene Therapy. 2002;9:270–281.

    Article  CAS  PubMed  Google Scholar 

  92. Brunori M, Malerba M, Kashiwazaki H, Iggo R . Replicating adenoviruses that target tumors with constitutive activation of the wnt signaling pathway. J Virol. 2001;75:2857–2865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tsukuda K, Wiewrodt R, Molnar-Kimber K, Jovanovic VP, Amin KM . An E2F-responsive replication-selective adenovirus targeted to the defective cell cycle in cancer cells: potent antitumoral efficacy but no toxicity to normal cell. Cancer Res. 2002;62:3438–3447.

    CAS  PubMed  Google Scholar 

  94. Wirth T, Zender L, Schulte B, et al. A telomerase-dependent conditionally replicating adenovirus for selective treatment of cancer. Cancer Res. 2003;63:3181–3188.

    CAS  PubMed  Google Scholar 

  95. Huang Q, Zhang X, Wang H, et al. A novel conditionally replicative adenovirus vector targeting telomerase-positive tumor cells. Clin Cancer Res. 2004;10:1439–1445.

    Article  CAS  PubMed  Google Scholar 

  96. Bauerschmitz GJ, Nettelbeck DM, Kanerva A, et al. The flt-1 promoter for transcriptional targeting of teratocarcinoma. Cancer Res. 2002;62:1271–1274.

    CAS  PubMed  Google Scholar 

  97. Post DE, Van Meir EG . A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene. 2003;22:2065–2072.

    Article  CAS  PubMed  Google Scholar 

  98. Doronin K, Kuppuswamy M, Toth K, et al. Tissue-specific, tumor-selective, replication-competent adenovirus vector for cancer gene therapy. J Virol. 2001;75:3314–3324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Miyatake S, Iyer A, Martuza RL, Rabkin SD . Transcriptional targeting of herpes simplex virus for cell-specific replication. J Virol. 1997;71:5124–5132.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Miyatake SI, Tani S, Feigenbaum F, et al. Hepatoma-specific antitumor activity of an albumin enhancer/promoter regulated herpes simplex virus in vivo. Gene Therapy. 1999;6:564–572.

    Article  CAS  PubMed  Google Scholar 

  101. Yamamura H, Hashio M, Noguchi M, et al. Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors. Cancer Res. 2001;61:3969–3977.

    CAS  PubMed  Google Scholar 

  102. Kasuya H, Pawlik TM, Mullen JT, et al. Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen. Cancer Res. 2004;64:2561–2567.

    Article  CAS  PubMed  Google Scholar 

  103. Malerba M, Daeffler L, Rommelaere J, Iggo RD . Replicating parvoviruses that target colon cancer cells. J Virol. 2003;77:6683–6691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Tollefson AE, Scaria A, Hermiston TW, Ryerse JS, Wold LJ, Wold WS . 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. 1996;70:2296–2306.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Doronin K, Toth K, Kuppuswamy M, Ward P, Tollefson AE, Wold WS . Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein. J Virol. 2000;74:6147–6155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Shtrichman R, Kleinberger T . Adenovirus type 5 E4 open reading frame 4 protein induces apoptosis in transformed cells. J Virol. 1998;72:2975–2982.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sauthoff H, Heitner S, Rom WN, Hay JG . Deletion of the adenoviral E1b-19kD gene enhances tumor cell killing of a replicating adenoviral vector. Hum Gene Ther. 2000;11:379–388.

    Article  CAS  PubMed  Google Scholar 

  108. Liu TC, Hallden G, Wang Y, et al. An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency. Mol Ther. 2004;9:786–803.

    Article  CAS  PubMed  Google Scholar 

  109. Galanis E, Bateman A, Johnson K, et al. Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas. Hum Gene Ther. 2001;12:811–821.

    Article  CAS  PubMed  Google Scholar 

  110. Nakamori M, Fu X, Meng F, et al. Effective therapy of metastatic ovarian cancer with an oncolytic herpes simplex virus incorporating two membrane fusion mechanisms. Clin Cancer Res. 2003;9:2727–2733.

    CAS  PubMed  Google Scholar 

  111. Nawa A, Nozawa N, Goshima F, et al. Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model. Gynecol Oncol. 2003;91:81–88.

    Article  CAS  PubMed  Google Scholar 

  112. Savage HE, Rossen RD, Hersh EM, Freedman RS, Bowen JM, Plager C . Antibody development to viral and allogeneic tumor cell-associated antigens in patients with malignant melanoma and ovarian carcinoma treated with lysates of virus-infected tumor cells. Cancer Res. 1986;46 (4 Part 2):2127–2133.

    CAS  PubMed  Google Scholar 

  113. Wallack MK, Sivanandham M, Balch CM, et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg. 1998;187:69–77.

    Article  CAS  PubMed  Google Scholar 

  114. Batliwalla FM, Bateman BA, Serrano D, et al. A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8T cell repertoire. Mol Med. 1998;4:783–794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Livingston PO, Albino AP, Chung TJ, et al. Serological response of melanoma patients to vaccines prepared from VSV lysates of autologous and allogeneic cultured melanoma cells. Cancer. 1985;55:713–720.

    Article  CAS  PubMed  Google Scholar 

  116. Eder JP, Kantoff PW, Roper K, et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res. 2000;6:1632–1638.

    CAS  PubMed  Google Scholar 

  117. Marshall JL, Hoyer RJ, Toomey MA, et al. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol. 2000;18:3964–3973.

    Article  CAS  PubMed  Google Scholar 

  118. Zhang JF, Hu C, Geng Y, 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. 1996;93:4513–4518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Andreansky S, He B, van Cott J, et al. Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins. Gene Therapy. 1998;5:121–130.

    Article  CAS  PubMed  Google Scholar 

  120. Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM . Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci USA. 2000;97:2208–2213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wong RJ, Patel SG, Kim S, et al. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. Hum Gene Ther. 2001;12:253–265.

    Article  CAS  PubMed  Google Scholar 

  122. Mastrangelo MJ, Maguire Jr HC, Eisenlohr LC, et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther. 1999;6:409–422.

    Article  CAS  PubMed  Google Scholar 

  123. Mukherjee S, Haenel T, Himbeck R, et al. Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation. Cancer Gene Ther. 2000;7:663–670.

    Article  CAS  PubMed  Google Scholar 

  124. Li Y, Yu DC, Chen Y, et al. A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin. Cancer Res. 2001;61:6428–6436.

    CAS  PubMed  Google Scholar 

  125. Yu DC, Chen Y, Dilley J, et al. Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Cancer Res. 2001;61:517–525.

    CAS  PubMed  Google Scholar 

  126. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH . ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med. 1997;3:639–645.

    Article  CAS  PubMed  Google Scholar 

  127. Heise C, Lemmon M, Kirn D . Efficacy with a replication-selective adenovirus plus cisplatin-based chemotherapy: dependence on sequencing but not p53 functional status or route of administration. Clin Cancer Res. 2000;6:4908–4914.

    CAS  PubMed  Google Scholar 

  128. Portella G, Scala S, Vitagliano D, Vecchio G, Fusco A . ONYX-015, an E1B gene-defective adenovirus, induces cell death in human anaplastic thyroid carcinoma cell lines. J Clin Endocrinol Metab. 2002;87:2525–2531.

    Article  CAS  PubMed  Google Scholar 

  129. You L, Yang CT, Jablons DM . ONYX-015 works synergistically with chemotherapy in lung cancer cell lines and primary cultures freshly made from lung cancer patients. Cancer Res. 2000;60:1009–1013.

    CAS  PubMed  Google Scholar 

  130. Khuri FR, Nemunaitis J, Ganly I, 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. Nat Med. 2000;6:879–885.

    Article  CAS  PubMed  Google Scholar 

  131. Hecht JR, Bedford R, Abbruzzese JL, et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res. 2003;9:555–561.

    CAS  PubMed  Google Scholar 

  132. Chahlavi A, Todo T, Martuza RL, Rabkin SD . Replication-competent herpes simplex virus vector G207 and cisplatin combination therapy for head and neck squamous cell carcinoma. Neoplasia. 1999;1:162–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cinatl Jr J, Cinatl J, Michaelis M, et al. Potent oncolytic activity of multimutated herpes simplex virus G207 in combination with vincristine against human rhabdomyosarcoma. Cancer Res. 2003;63:1508–1514.

    CAS  PubMed  Google Scholar 

  134. Chen Y, DeWeese T, Dilley J, et al. CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Res. 2001;61:5453–5460.

    CAS  PubMed  Google Scholar 

  135. Advani SJ, Sibley GS, Song PY, et al. Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors. Gene Therapy. 1998;5:160–165.

    Article  CAS  PubMed  Google Scholar 

  136. Bradley JD, Kataoka Y, Advani S, et al. Ionizing radiation improves survival in mice bearing intracranial high-grade gliomas injected with genetically modified herpes simplex virus. Clin Cancer Res. 1999;5:1517–1522.

    CAS  PubMed  Google Scholar 

  137. Chung SM, Advani SJ, Bradley JD, et al. The use of a genetically engineered herpes simplex virus (R7020) with ionizing radiation for experimental hepatoma. Gene Therapy. 2002;9:75–80.

    Article  CAS  PubMed  Google Scholar 

  138. Blank SV, Rubin SC, Coukos G, Amin KM, Albelda SM, Molnar-Kimber KL . Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation. Hum Gene Ther. 2002;13:627–639.

    Article  CAS  PubMed  Google Scholar 

  139. Jorgensen TJ, Katz S, Wittmack EK, 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. 2001;3:451–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Nanda D, Vogels R, Havenga M, Avezaat CJ, Bout A, Smitt PS . Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. Cancer Res. 2001;61:8743–8750.

    CAS  PubMed  Google Scholar 

  141. Wildner O, Blaese RM, Morris JC . Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of herpes simplex virus-thymidine kinase. Cancer Res. 1999;59:410–413.

    CAS  PubMed  Google Scholar 

  142. Morris JC, Wildner O . Therapy of head and neck squamous cell carcinoma with an oncolytic adenovirus expressing HSV-tk. Mol Ther. 2000;1:56–62.

    Article  CAS  PubMed  Google Scholar 

  143. Wildner O, Morris JC . Therapy of peritoneal carcinomatosis from colon cancer with oncolytic adenoviruses. J Gene Med. 2000;2:353–360.

    Article  CAS  PubMed  Google Scholar 

  144. Lambright ES, Amin K, Wiewrodt R, et al. Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy. Gene Therapy. 2001;8:946–953.

    Article  CAS  PubMed  Google Scholar 

  145. Hajri A, Wack S, Dinsart C, Cornelis JJ, Rommelaere J, Aprahamian M . Autonomous parvovirus H1-mediated combination suicide and cytokine gene therapy for pancreatic adenocarcinoma. Pancreatology. 2002;2:217–361.

    Article  Google Scholar 

  146. Zhang ZL, Zou WG, Luo CX, et al. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res. 2003;13:481–489.

    Article  CAS  PubMed  Google Scholar 

  147. Porosnicu M, Mian A, Barber GN . The oncolytic effect of recombinant vesicular stomatitis virus is enhanced by expression of the fusion cytosine deaminase/uracil phosphoribosyltransferase suicide gene. Cancer Res. 2003;63:8366–8376.

    CAS  PubMed  Google Scholar 

  148. Freytag SO, Rogulski KR, Paielli DL, Gilbert JD, Kim JH . A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum Gene Ther. 1998;9:1323–1333.

    Article  CAS  PubMed  Google Scholar 

  149. Rogulski KR, Wing MS, Paielli DL, Gilbert JD, Kim JH, Freytag SO . Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization. Hum Gene Ther. 2000;11:67–76.

    Article  CAS  PubMed  Google Scholar 

  150. Freytag SO, Khil M, Stricker H, et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res. 2002;62:4968–4976.

    CAS  PubMed  Google Scholar 

  151. Chase M, Chung RY, Chiocca EA . An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy. Nat Biotechnol. 1998;16:444–448.

    Article  CAS  PubMed  Google Scholar 

  152. Pawlik TM, Nakamura H, Yoon SS, et al. Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. Cancer Res. 2000;60:2790–2795.

    CAS  PubMed  Google Scholar 

  153. Pawlik TM, Nakamura H, Mullen JT, et al. Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene. Cancer. 2002;95:1171–1181.

    Article  CAS  PubMed  Google Scholar 

  154. Aghi M, Chou TC, Suling K, Breakefield XO, Chiocca EA . 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. 1999;59:3861–3865.

    CAS  PubMed  Google Scholar 

  155. Freytag SO, Stricker H, Pegg J, et al. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res. 2003;63:7497–7506.

    CAS  PubMed  Google Scholar 

  156. Kanazawa T, Mizukami H, Okada T, et al. Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice. Gene Therapy. 2003;10:51–58.

    Article  CAS  PubMed  Google Scholar 

  157. Toda M, Rabkin SD, Kojima H, Martuza RL . Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. Hum Gene Ther. 1999;10:385–393.

    Article  CAS  PubMed  Google Scholar 

  158. Todo T, Rabkin SD, Sundaresan P, et al. Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus. Hum Gene Ther. 1999;10:2741–2755.

    Article  CAS  PubMed  Google Scholar 

  159. 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. 2002;9:356–364.

    Article  CAS  PubMed  Google Scholar 

  160. Ikeda K, Ichikawa T, Wakimoto H, et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nat Med. 1999;5:881–887.

    Article  CAS  PubMed  Google Scholar 

  161. Heise CC, Williams A, Olesch J, Kirn DH . Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: intratumoral spread and distribution effects. Cancer Gene Ther. 1999;6:499–504.

    Article  CAS  PubMed  Google Scholar 

  162. Sherr CJ . The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 2000;60:3689–3695.

    CAS  PubMed  Google Scholar 

  163. Wong RJ, Chan MK, Yu Z, et al. Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12. Clin Cancer Res. 2004;10 (1 Part 1):251–259.

    Article  CAS  PubMed  Google Scholar 

  164. Lamfers ML, Grill J, Dirven CM, et al. Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy. Cancer Res. 2002;62:5736–5742.

    CAS  PubMed  Google Scholar 

  165. McCart JA, Puhlmann M, Lee J, et al. Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression. Gene Therapy. 2000;7:1217–1223.

    Article  CAS  PubMed  Google Scholar 

  166. Gulley J, Chen AP, Dahut W, et al. Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. Prostate. 2002;53:109–117.

    Article  CAS  PubMed  Google Scholar 

  167. Csatary LK, Gosztonyi G, Szeberenyi J, et al. MTH-68/H oncolytic viral treatment in human high-grade gliomas. J Neurooncol. 2004;67:83–93.

    Article  CAS  PubMed  Google Scholar 

  168. Oncolytics Biotech releases REOLYSIN phase I clinical trial results. Expert Rev Anticancer Ther. 2002;2:139.

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Everts, B., van der Poel, H. Replication-selective oncolytic viruses in the treatment of cancer. Cancer Gene Ther 12, 141–161 (2005). https://doi.org/10.1038/sj.cgt.7700771

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