Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Cancer Gene Therapy volume 11, pages 555–569 (2004)Cite this article

Abstract

A potentially promising treatment of metastatic cancer is the systemic delivery of oncolytic adenoviruses. This requires engineering viruses which selectively replicate in tumors. We have constructed such an oncolytic adenovirus, OAS403, in which two early region genes are under the control of tumor-selective promoters that play a role in two key pathways involved in tumorigenesis. The early region E1A is controlled by the promoter for the E2F-1 gene, a transcription factor that primarily upregulates genes for cell growth. The E4 region is under control of the promoter for human telomerase reverse transcriptase, a gene upregulated in most cancer cells. OAS403 was evaluated in vitro on a panel of human cells and found to elicit tumor-selective cell killing. Also, OAS403 was less toxic in human hepatocyte cultures, as well as in vivo when compared to an oncolytic virus that lacked selective E4 control. A single intravenous injection of 3 × 1012 vp/kg in a Hep3B xenograft mouse tumor model led to significant antitumor efficacy. Additionally, systemic administration in a pre-established LNCaP prostate tumor model resulted in over 80% complete tumor regressions at a tolerable dose. Vector genome copy number was measured in tumors and livers at various times following tail vein injection and showed a selective time-dependent increase in tumors but not livers over 29 days. Furthermore, efficacy was significantly improved when OAS403 treatment was combined with doxorubicin. This virus holds promise for the treatment of a broad range of human cancers including metastatic disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Alemany R, Balague C, Curiel DT . Replicative adenoviruses for cancer therapy. Nat Biotechnol. 2000;18:723–727.

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Hawkins LK, Lemoine NR, Kirn D . Oncolytic biotherapy: a novel therapeutic platform. Lancet Oncol. 2002;3:17–26.

    Article  CAS  PubMed  Google Scholar 

  4. Jakubczak JL, Ryan P, Gorziglia M, et al. An oncolytic adenovirus selective for retinoblastoma tumor suppressor protein pathway-defective tumors: dependence on E1A, the E2F-1 promoter, and viral replication for selectivity and efficacy. Cancer Res. 2003;63:1490–1499.

    CAS  PubMed  Google Scholar 

  5. Russell WC . Update on adenovirus and its vectors. J Gen Virol. 2000;81(Part 11):2573–2604.

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. 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 

  8. Peng XY, Won JH, Rutherford T, et al. The use of the L-plastin promoter for adenoviral-mediated, tumor-specific gene expression in ovarian and bladder cancer cell lines. Cancer Res. 2001;61:4405–4413.

    CAS  PubMed  Google Scholar 

  9. 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 

  10. 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 

  11. 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 

  12. DeWeese TL, van der PH, 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 

  13. Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: Biological principles, risk management and future directions. Nat Med. 2001;7:781–787.

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Tauber B, Dobner T . Adenovirus early E4 genes in viral oncogenesis. Oncogene. 2001;20:7847–7854.

    Article  CAS  PubMed  Google Scholar 

  16. Gorziglia MI, Lapcevich C, Roy S, et al. Generation of an adenovirus vector lacking E1, E2a, E3, and all of E4 except open reading frame 3. J Virol. 1999;73:6048–6055.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Halbert DN, Cutt JR, Shenk T . Adenovirus early region 4 encodes functions required for efficient DNA replication, late gene expression, and host cell shutoff. J Virol. 1985;56:250–257.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaelin WGJ . Functions of the retinoblastoma protein. BioEssays. 1999;21:950–958.

    Article  PubMed  Google Scholar 

  19. Trimarchi JM, Lees JA . Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002;3:11–20.

    Article  CAS  PubMed  Google Scholar 

  20. Dyson N . The regulation of E2F by pRB-family proteins. Genes Dev. 1998;12:2245–2262.

    Article  CAS  PubMed  Google Scholar 

  21. Adams PD, Kaelin WGJ . Transcriptional control by E2F. Semin Cancer Biol. 1995;6:99–108.

    Article  CAS  PubMed  Google Scholar 

  22. Zwicker J, Muller R . Cell cycle-regulated transcription in mammalian cells. Prog Cell Cycle Res. 1995;1:91–99.

    Article  CAS  PubMed  Google Scholar 

  23. Nakayama J, Tahara H, Tahara E, et al. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet. 1998;18:65–68.

    Article  CAS  PubMed  Google Scholar 

  24. Takakura M, Kyo S, Kanaya T, et al. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999;59:551–557.

    CAS  PubMed  Google Scholar 

  25. Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–795.

    Article  CAS  PubMed  Google Scholar 

  26. Gunes C, Lichtsteiner S, Vasserot AP, Englert C . Expression of the hTERT gene is regulated at the level of transcriptional initiation and repressed by Mad1. Cancer Res. 2000;60:2116–2121.

    CAS  PubMed  Google Scholar 

  27. Kolquist KA, Ellisen LW, Counter CM, et al. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet. 1998;19:182–186.

    Article  CAS  PubMed  Google Scholar 

  28. Poole JC, Andrews LG, Tollefsbol TO . Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT). Gene. 2001;269:1–12.

    Article  CAS  PubMed  Google Scholar 

  29. Braunstein I, Cohen-Barak O, Shachaf C, et al. Human telomerase reverse transcriptase promoter regulation in normal and malignant human ovarian epithelial cells. Cancer Res. 2001;61:5529–5536.

    CAS  PubMed  Google Scholar 

  30. Gu J, Kagawa S, Takakura M, et al. Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers. Cancer Res. 2000;60:5359–5364.

    CAS  PubMed  Google Scholar 

  31. Komata T, Kondo Y, Kanzawa T, et al. Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter. Cancer Res. 2001;61:5796–5802.

    CAS  PubMed  Google Scholar 

  32. Komata T, Kondo Y, Kanzawa T, et al. Caspase-8 gene therapy using the human telomerase reverse transcriptase promoter for malignant glioma cells. Hum Gene Ther. 2002;13:1015–1025.

    Article  CAS  PubMed  Google Scholar 

  33. Majumdar AS, Hughes DE, Lichtsteiner SP, Wang Z, Lebkowski JS, Vasserot AP . The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters. Gene Therapy. 2001;8:568–578.

    Article  CAS  PubMed  Google Scholar 

  34. Kim E, Kim JH, Shin HY, Lee H, Yang JM, Kim J, et al. Ad-mTERT-delta19, a conditional replication-competent adenovirus driven by the human telomerase promoter, selectively replicates in and elicits cytopathic effect in a cancer cell-specific manner. Hum Gene Ther. 2003;14:1415–1428.

    Article  CAS  PubMed  Google Scholar 

  35. Huang TG, Savontaus MJ, Shinozaki K, Sauter BV, Woo SL . Telomerase-dependent oncolytic adenovirus for cancer treatment. Gene Therapy. 2003;10:1241–1247.

    Article  CAS  PubMed  Google Scholar 

  36. Irving J, Wang Z, Powell S, et al. Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity. Cancer Gene Ther. 2004;11:174–185.

    Article  CAS  PubMed  Google Scholar 

  37. Farshid M, Hsia CC, Tabor E . Alterations of the RB tumour suppressor gene in hepatocellular carcinoma and hepatoblastoma cell lines in association with abnormal p53 expression. J Viral Hepat. 1994;1:45–53.

    Article  CAS  PubMed  Google Scholar 

  38. Spillare EA, Okamoto A, Hagiwara K, et al. Suppression of growth in vitro and tumorigenicity in vivo of human carcinoma cell lines by transfected p16INK4. Mol Carcinog. 1996;16:53–60.

    Article  CAS  PubMed  Google Scholar 

  39. Thalmann GN, Sikes RA, Wu TT, et al. LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate. 2000;44:91–103.

    Article  CAS  PubMed  Google Scholar 

  40. Korenchuk S, Lehr JE, MClean L, et al. VCaP, a cell-based model system of human prostate cancer. In Vivo. 2001;15:163–168.

    CAS  PubMed  Google Scholar 

  41. Young CSH, Shenk T, Ginsberg HS . The Genetic System. In: Ginsberg HS, ed. The Adenoviruses. New York: Plenum Press; 1984: 125–172.

    Chapter  Google Scholar 

  42. Chartier C, Degryse E, Gantzer M, Dieterle A, Pavirani A, Mehtali M . Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J Virol. 1996;70:4805–4810.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA. 1998;95:2509–2514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jakubczak JL, Rollence ML, Stewart DA, et al. Adenovirus type 5 viral particles pseudotyped with mutagenized fiber proteins show diminished infectivity of coxsackie B-adenovirus receptor-bearing cells. J Virol. 2001;75:2972–2981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. J Virol. 1996;70:7498–7509.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Smith T, Idamakanti N, Kylefjord H, et al. In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor. Mol Ther. 2002;5:770–779.

    Article  CAS  PubMed  Google Scholar 

  47. Paielli DL, Wing MS, Rogulski KR, et al. Evaluation of the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse. Mol Ther. 2000;1:263–274.

    Article  CAS  PubMed  Google Scholar 

  48. Parr MJ, Manome Y, Tanaka T, et al. Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector. Nat Med. 1997;3:1145–1149.

    Article  CAS  PubMed  Google Scholar 

  49. Kelly WR . The liver and biliary system. In: Jubb KVF, Kennedy PC, Palmer N, eds. Pathology of Domestic Animals. 4th edn. New York: Academic Press; 1993: 319–406.

    Chapter  Google Scholar 

  50. Mansfield K, King N . Viral Diseases. In: Bennett BT, Abee CR, Henrickson R, eds. Nonhuman Primates in Biomedical Research. New York: Academic Press; 1998: 1–57.

    Google Scholar 

  51. Porter HJ, Padfield CJ, Peres LC, Hirschowitz L, Berry PJ . Adenovirus and intranuclear inclusions in appendices in intussusception. J Clin Pathol. 1993;46:154–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Greenberg RA, Allsopp RC, Chin L, Morin GB, DePinho RA . Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene. 1998;16:1723–1730.

    Article  CAS  PubMed  Google Scholar 

  53. Yin L, Hubbard AK, Giardina C . NF-kappa B regulates transcription of the mouse telomerase catalytic subunit. J Biol Chem. 2000;275:36671–36675.

    Article  CAS  PubMed  Google Scholar 

  54. Smith TA, Mehaffey MG, Kayda DB, et al. Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice. Nat Genet. 1993;5:397–402.

    Article  CAS  PubMed  Google Scholar 

  55. Bristol JA, Shirley P, Idamakanti N, Kaleko M, Connelly S . In vivo dose threshold effect of adenovirus-mediated factor VIII gene therapy in hemophiliac mice. Mol Ther. 2000;2:223–232.

    Article  CAS  PubMed  Google Scholar 

  56. Tao N, Gao GP, Parr M, et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther. 2001;3:28–35.

    Article  CAS  PubMed  Google Scholar 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. Bernt KM, Steinwaerder DS, Ni S, Li ZY, Roffler SR, Lieber A . Enzyme-activated prodrug therapy enhances tumor-specific replication of adenovirus vectors. Cancer Res. 2002;62:6089–6098.

    CAS  PubMed  Google Scholar 

  62. Mi J, Li ZY, Ni S, Steinwaerder D, Lieber A . Induced apoptosis supports spread of adenovirus vectors in tumors. Hum Gene Ther. 2001;12:1343–1352.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the GTI Histology, Molecular Biology, and Cell Biology Core Labs and the Laboratory Animal Services group for technical assistance. We also thank Dr Bill Kaelin for the E2F-1 promoter and helpful discussion. We gratefully acknowledge Dr Alex Matter, Novartis Oncology, for his guidance and support. This publication is fondly dedicated to the memory of our friend and colleague Pamela S Shirley.

Author information

Author notes

  1. Lynda K Hawkins, Shanthi Ganesh & P Seshidhar Reddy

    Present address: Cell Genesys, Inc., 500 Forbes Blvd., South San Francisco, CA, 94080, USA

  2. Paul L Hallenbeck

    Present address: NeotropiX, Inc., 7461 Rosewood Manor Lane, Gaithersburg, MD, 20882, USA

Authors and Affiliations

  1. Genetic Therapy, Inc. (a Novartis Company), Gaithersburg, Maryland, 20878, USA

    Patricia C Ryan, John L Jakubczak, David A Stewart, Lynda K Hawkins, Cheng Cheng, Lori M Clarke, Shanthi Ganesh, Carl Hay, Ying Huang, Michele Kaloss, Anthony Marinov, Sandrina S Phipps, P Seshidhar Reddy, Pamela S Shirley, Yelena Skripchenko, Ling Xu, Jingping Yang, Suzanne Forry-Schaudies & Paul L Hallenbeck

Authors
  1. Patricia C Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John L Jakubczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David A Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lynda K Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lori M Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shanthi Ganesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carl Hay
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michele Kaloss
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anthony Marinov
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sandrina S Phipps
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P Seshidhar Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Pamela S Shirley
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yelena Skripchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ling Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jingping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Suzanne Forry-Schaudies
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Paul L Hallenbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul L Hallenbeck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ryan, P., Jakubczak, J., Stewart, D. et al. Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer. Cancer Gene Ther 11, 555–569 (2004). https://doi.org/10.1038/sj.cgt.7700735

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700735

Keywords

This article is cited by

Search

Advanced search

Quick links