Abstract
Oncolytic adenoviruses have been safe in clinical trials but the efficacy has been mostly limited. All published trials have been performed with serotype 5 based viruses. The expression level of the Ad5 receptor CAR may be variable in advanced tumors. In contrast, the Ad3 receptor remains unclear, but is known to be abundantly expressed in most tumors. Therefore, we hypothesized that a fully serotype 3 oncolytic adenovirus might be useful for treating cancer. Patients exposed to adenoviruses develop high titers of serotype-specific neutralizing antibodies, which might compromise re-administration. Thus, having different serotype oncolytic viruses available might facilitate repeated dosing in humans. Ad3-hTERT-E1A is a fully serotype 3 oncolytic adenovirus controlled by the promoter of the catalytic domain of human telomerase. It was effective in vitro on cell lines representing seven major cancer types, although low toxicity was seen in non-malignant cells. In vivo, the virus had anti-tumor efficacy in three different animal models. Although in vitro oncolysis mediated by Ad3-hTERT-E1A and wild-type Ad3 occurred more slowly than with Ad5 or Ad5/3 (Ad3 fiber knob in Ad5) based viruses, in vivo the virus was at least as potent as controls. Anti-tumor efficacy was retained in presence of neutralizing anti-Ad5 antibodies whereas Ad5 based controls were blocked. In summary, we report generation of a non-Ad5 based oncolytic adenovirus, which might be useful for testing in cancer patients, especially in the context of high anti-Ad5 neutralizing antibodies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Vaha-Koskela MJ, Heikkila JE, Hinkkanen AE . Oncolytic viruses in cancer therapy. Cancer Lett 2007; 254: 178–216.
Alemany R . Cancer selective adenoviruses. Mol Aspects Med 2007; 28: 42–58.
Liu TC, Thorne SH, Kirn DH . Oncolytic adenoviruses for cancer gene therapy. Methods Mol Biol 2008; 433: 243–258.
Nettelbeck DM . Cellular genetic tools to control oncolytic adenoviruses for virotherapy of cancer. J Mol Med 2008; 86: 363–377.
Bilbao R, Bustos M, Alzuguren P, Pajares MJ, Drozdzik M, Qian C et al. A blood-tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds. Gene Ther 2000; 7: 1824–1832.
Sauthoff H, Hu J, Maca C, Goldman M, Heitner S, Yee H et al. Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points. Hum Gene Ther 2003; 14: 425–433.
Chen Y, Yu DC, Charlton D, Henderson DR . 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 2000; 11: 1553–1567.
Sarkioja M, Pesonen S, Raki M, Hakkarainen T, Salo J, Ahonen MT et al. Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies. Gene Ther 2008; 15: 921–929.
Kuhn I, Harden P, Bauzon M, Chartier C, Nye J, Thorne S et al. Directed evolution generates a novel oncolytic virus for the treatment of colon cancer. PLoS ONE 2008; 3: e2409.
Sandberg L, Papareddy P, Silver J, Bergh A, Mei YF . Replication-competent Ad11p vector (RCAd11p) efficiently transduces and replicates in hormone-refractory metastatic prostate cancer cells. Hum Gene Ther 2009; 20: 361–373.
Kangasniemi L, Kiviluoto T, Kanerva A, Raki M, Ranki T, Sarkioja M et al. Infectivity-enhanced adenoviruses deliver efficacy in clinical samples and orthotopic models of disseminated gastric cancer. Clin Cancer Res 2006; 12: 3137–3144.
Rajecki M, Kanerva A, Stenman UH, Tenhunen M, Kangasniemi L, Sarkioja M et al. Treatment of prostate cancer with Ad5/3Delta24hCG allows non-invasive detection of the magnitude and persistence of virus replication in vivo. Mol Cancer Ther 2007; 6: 742–751.
Yu L, Shimozato O, Li Q, Kawamura K, Ma G, Namba M et al. Adenovirus type 5 substituted with type 11 or 35 fiber structure increases its infectivity to human cells enabling dual gene transfer in CD46-dependent and -independent manners. Anticancer Res 2007; 27: 2311–2316.
Mizuguchi H, Hayakawa T . Adenovirus vectors containing chimeric type 5 and type 35 fiber proteins exhibit altered and expanded tropism and increase the size limit of foreign genes. Gene 2002; 285: 69–77.
Kanerva A, Mikheeva GV, Krasnykh V, Coolidge CJ, Lam JT, Mahasreshti PJ et al. Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells. Clin Cancer Res 2002; 8: 275–280.
Mastrangeli A, Harvey BG, Yao J, Wolff G, Kovesdi I, Crystal RG et al. ‘Sero-switch’ adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. Hum Gene Ther 1996; 7: 79–87.
Tuve S, Wang H, Jacobs JD, Yumul RC, Smith DF, Lieber A . Role of cellular heparan sulfate proteoglycans in infection of human adenovirus serotype 3 and 35. PLoS Pathog 2008; 4: e1000189.
Sirena D, Ruzsics Z, Schaffner W, Greber UF, Hemmi S . The nucleotide sequence and a first generation gene transfer vector of species B human adenovirus serotype 3. Virology 2005; 343: 283–298.
Short JJ, Vasu C, Holterman MJ, Curiel DT, Pereboev A . Members of adenovirus species B utilize CD80 and CD86 as cellular attachment receptors. Virus Res 2006; 122: 144–153.
Tuve S, Wang H, Ware C, Liu Y, Gaggar A, Bernt K et al. A new group B adenovirus receptor is expressed at high levels on human stem and tumor cells. J Virol 2006; 80: 12109–12120.
Volk AL, Rivera AA, Kanerva A, Bauerschmitz G, Dmitriev I, Nettelbeck DM et al. Enhanced adenovirus infection of melanoma cells by fiber-modification: incorporation of RGD peptide or Ad5/3 chimerism. Cancer Biol Ther 2003; 2: 511–515.
Ramirez PJ, Vickers SM, Ono HA, Davydova J, Takayama K, Thompson TC et al. Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model. Am J Surg 2008; 195: 481–490.
Hoffmann D, Bayer W, Heim A, Potthoff A, Nettelbeck DM, Wildner O . Evaluation of twenty-one human adenovirus types and one infectivity-enhanced adenovirus for the treatment of malignant melanoma. J Invest Dermatol 2008; 128: 988–998.
Zhu ZB, Mathis JM, Makhija SK, Lu B, Wang M, Ji S et al. Targeting of a conditionally replicative adenovirus agent to human squamous cell carcinomas of the head and neck. Int J Oncol 2007; 31: 1213–1222.
Ulasov IV, Rivera AA, Han Y, Curiel DT, Zhu ZB, Lesniak MS . Targeting adenovirus to CD80 and CD86 receptors increases gene transfer efficiency to malignant glioma cells. J Neurosurg 2007; 107: 617–627.
Rein DT, Breidenbach M, Curiel DT . Current developments in adenovirus-based cancer gene therapy. Future Oncol 2006; 2: 137–143.
Kawakami Y, Li H, Lam JT, Krasnykh V, Curiel DT, Blackwell JL . Substitution of the adenovirus serotype 5 knob with a serotype 3 knob enhances multiple steps in virus replication. Cancer Res 2003; 63: 1262–1269.
Takayama K, Reynolds PN, Short JJ, Kawakami Y, Adachi Y, Glasgow JN et al. A mosaic adenovirus possessing serotype Ad5 and serotype Ad3 knobs exhibits expanded tropism. Virology 2003; 309: 282–293.
Fields BN, Knipe DM, Howley PM . Fields' virology, 5th edn. Volume: 2. Wolters Kluwer Health/Lippincott Williams & Wilkins: Philadelphia, 2007, (xix, 3091, 3086s)pp.
Fujiwara T, Urata Y, Tanaka N . Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter. Curr Cancer Drug Targets 2007; 7: 191–201.
Wang Y, Huang F, Cai H, Zhong S, Liu X, Tan WS . Potent antitumor effect of TRAIL mediated by a novel adeno-associated viral vector targeting to telomerase activity for human hepatocellular carcinoma. J Gene Med 2008; 10: 518–526.
Huang P, Watanabe M, Kaku H, Kashiwakura Y, Chen J, Saika T et al. Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model. Cancer Gene Ther 2008; 15: 315–322.
Davis JJ, Wang L, Dong F, Zhang L, Guo W, Teraishi F et al. Oncolysis and suppression of tumor growth by a GFP-expressing oncolytic adenovirus controlled by an hTERT and CMV hybrid promoter. Cancer Gene Ther 2006; 13: 720–723.
Mohammadi ES, Ketner EA, Johns DC, Ketner G . Expression of the adenovirus E4 34k oncoprotein inhibits repair of double strand breaks in the cellular genome of a 293-based inducible cell line. Nucleic Acids Res 2004; 32: 2652–2659.
Sarkioja M, Kanerva A, Salo J, Kangasniemi L, Eriksson M, Raki M et al. Noninvasive imaging for evaluation of the systemic delivery of capsid-modified adenoviruses in an orthotopic model of advanced lung cancer. Cancer 2006; 107: 1578–1588.
Bauerschmitz GJ, Ranki T, Kangasniemi L, Ribacka C, Eriksson M, Porten M et al. Tissue-specific promoters active in CD44+CD24-/low breast cancer cells. Cancer Res 2008; 68: 5533–5539.
Hakkarainen T, Rajecki M, Sarparanta M, Tenhunen M, Airaksinen AJ, Desmond RA et al. Targeted radiotherapy for prostate cancer with an oncolytic adenovirus coding for human sodium iodide symporter. Clin Cancer Res 2009; 15: 5396–5403.
Dhar D, Spencer JF, Toth K, Wold WS . Effect of preexisting immunity on oncolytic adenovirus vector INGN 007 antitumor efficacy in immunocompetent and immunosuppressed Syrian hamsters. J Virol 2009; 83: 2130–2139.
Pesonen S, Nokisalmi P, Escutenaire S, Sarkioja M, Raki M, Cerullo V et al. Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2 L-D24 in patients with metastatic and refractory solid tumors. Gene Ther 2010; 17: 892–904.
Cerullo V, Pesonen S, Diaconu I, Escutenaire S, Arstila PT, Ugolini M et al. Oncolytic adenovirus coding for granulocyte macrophage colony-stimulating factor induces antitumoral immunity in cancer patients. Cancer Res 2010; 70: 4297–4309.
Koski A, Kangasniemi L, Escutenaire S, Pesonen S, Cerullo V, Diaconu I et al. Treatment of cancer patients with a serotype 5/3 chimeric oncolytic adenovirus expressing GMCSF. Mol Ther 2010; 18: 1874–1884.
Shen BH, Bauzon M, Hermiston TW . The effect of hypoxia on the uptake, replication and lytic potential of group B adenovirus type 3 (Ad3) and type 11p (Ad11p). Gene Ther 2006; 13: 986–990.
Fujiwara T, Urata Y, Tanaka N . Diagnostic and therapeutic application of telomerase-specific oncolytic adenoviral agents. Front Biosci 2008; 13: 1881–1886.
Kanerva A, Hemminki A . Modified adenoviruses for cancer gene therapy. Int J Cancer 2004; 110: 475–480.
Ouchi M, Kawamura H, Urata Y, Fujiwara T . Antiviral activity of cidofovir against telomerase-specific replication-selective oncolytic adenovirus, OBP-301 (Telomelysin). Invest New Drugs 2008; 27: 241–245.
Hakkarainen T, Sarkioja M, Lehenkari P, Miettinen S, Ylikomi T, Suuronen R et al. Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors. Hum Gene Ther 2007; 18: 627–641.
Eriksson M, Guse K, Bauerschmitz G, Virkkunen P, Tarkkanen M, Tanner M et al. Oncolytic adenoviruses kill breast cancer initiating CD44+CD24-/low cells. Mol Ther 2007; 15: 2088–2093.
Kanerva A, Zinn KR, Chaudhuri TR, Lam JT, Suzuki K, Uil TG et al. Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus. Mol Ther 2003; 8: 449–458.
Acknowledgements
We thank Eerika Karli, Aila Karioja-Kallio, Kikka Holm and Päivi Hannuksela for expert assistance. This study was supported by National Graduate School of Clinical Investigation, the European Research Council, EU FP6 APOTHERAPY and THERADPOX, HUCH Research Funds (EVO), Finnish Cancer Society, Sigrid Juselius Foundation, Academy of Finland, Biocentrum Helsinki and University of Helsinki. Silvio Hemmi is supported by the Cancer Society of the Kanton Zurich, Switzerland. Akseli Hemminki is K. Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Work for this publication has been done in Helsinki Biomedicum, Helsinki, Finland.
Supplementary Information accompanies the paper on Cancer Gene Therapy website
Rights and permissions
About this article
Cite this article
Hemminki, O., Bauerschmitz, G., Hemmi, S. et al. Oncolytic adenovirus based on serotype 3. Cancer Gene Ther 18, 288–296 (2011). https://doi.org/10.1038/cgt.2010.79
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cgt.2010.79
Keywords
This article is cited by
-
Effects of pre-existing anti-adenovirus antibodies on transgene expression levels and therapeutic efficacies of arming oncolytic adenovirus
Scientific Reports (2022)
-
Ad5/3 is able to avoid neutralization by binding to erythrocytes and lymphocytes
Cancer Gene Therapy (2021)
-
A potential bat adenovirus-based oncolytic virus targeting canine cancers
Scientific Reports (2021)
-
Oncolytic viruses for cancer immunotherapy
Journal of Hematology & Oncology (2020)
-
Mapping of Adenovirus of serotype 3 fibre interaction to desmoglein 2 revealed a novel ‘non-classical’ mechanism of viral receptor engagement
Scientific Reports (2018)