Abstract
Oncolytic viruses kill cancer cells by tumor-selective replication. Clinical data have established the safety of the approach but also the need of improvements in potency. Efficacy of oncolysis is linked to effective infection of target cells and subsequent productive replication. Other variables include intratumoral barriers, access to target cells, uptake by non-target organs and immune response. Each of these aspects relates to the location and degree of virus replication. Unfortunately, detection of in vivo replication has been difficult, labor intensive and costly and therefore not much studied. We hypothesized that by coinfection of a luciferase expressing E1-deleted virus with an oncolytic virus, both viruses would replicate when present in the same cell. Photon emission due to conversion of D-Luciferin is sensitive and penetrates tissues well. Importantly, killing of animals is not required and each animal can be imaged repeatedly. Two different murine xenograft models were used and intratumoral coinjections of luciferase encoding virus were performed with eight different oncolytic adenoviruses. In both models, we found significant correlation between photon emission and infectious virus production. This suggests that the system can be used for non-invasive quantitation of the amplitude, persistence and dynamics of oncolytic virus replication in vivo, which could be helpful for the development of more effective and safe agents.
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References
Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.
Kanerva A, Hemminki A . Adenoviruses for treatment of cancer. Ann Med 2005; 37: 33–43.
Immonen A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 2004; 10: 967–972.
Xia ZJ, Chang JH, Zhang L, Jiang WQ, Guan ZZ, Liu JW et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng 2004; 23: 1666–1670.
Peng Z . Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 2005; 16: 1016–1027.
Kanerva A, Hemminki A . Modified adenoviruses for cancer gene therapy. Int J Cancer 2004; 110: 475–480.
Puumalainen AM, Vapalahti M, Agrawal RS, Kossila M, Laukkanen J, Lehtolainen P et al. Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 1998; 9: 1769–1774.
Kirn D . Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned? Gene Therapy 2001; 8: 89–98.
Hemminki A, Dmitriev I, Liu B, Desmond RA, Alemany R, Curiel DT . Targeting oncolytic adenoviral agents to the epidermal growth factor pathway with a secretory fusion molecule. Cancer Res 2001; 61: 6377–6381.
Alemany R, Lai S, Lou YC, Jan HY, Fang X, Zhang WW . Complementary adenoviral vectors for oncolysis. Cancer Gene Ther 1999; 6: 21–25.
Umeoka T, Kawashima T, Kagawa S, Teraishi F, Taki M, Nishizaki M et al. Visualization of intrathoracically disseminated solid tumors in mice with optical imaging by telomerase-specific amplification of a transferred green fluorescent protein gene. Cancer Res 2004; 64: 6259–6265.
Thorne SH, Tam BY, Kirn DH, Contag CH, Kuo CJ . Selective intratumoral amplification of an antiangiogenic vector by an oncolytic virus produces enhanced antivascular and anti-tumor efficacy. Mol Ther 2006; 13: 938–946.
Habib NA, Mitry R, Seth P, Kuppuswamy M, Doronin K, Toth K et al. Adenovirus replication-competent vectors (KD1, KD3) complement the cytotoxicity and transgene expression from replication-defective vectors (Ad-GFP, Ad-Luc). Cancer Gene Ther 2002; 9: 651–654.
Suzuki K, Alemany R, Yamamoto M, Curiel DT . The presence of the adenovirus E3 region improves the oncolytic potency of conditionally replicative adenoviruses. Clin Cancer Res 2002; 8: 3348–3359.
Hemminki A, Wang M, Hakkarainen T, Desmond RA, Wahlfors J, Curiel DT . Production of an EGFR targeting molecule from a conditionally replicating adenovirus impairs its oncolytic potential. Cancer Gene Ther 2003; 10: 583–588.
Hakkarainen T, Hemminki A, Curiel DT, Wahlfors J . A conditionally replicative adenovirus that codes for a TK-GFP fusion protein (Ad5Delta24TK-GFP) for evaluation of the potency of oncolytic virotherapy combined with molecular chemotherapy. Int J Mol Med 2006; 18: 751–759.
Hemminki A, Zinn KR, Liu B, Chaudhuri TR, Desmond RA, Rogers BE et al. In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus. J Natl Cancer Inst 2002; 94: 741–749.
Kanerva A, Wang M, Bauerschmitz GJ, Lam JT, Desmond RA, Bhoola SM et al. Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses. Mol Ther 2002; 5: 695–704.
Bauerschmitz GJ, Lam JT, Kanerva A, Suzuki K, Nettelbeck DM, Dmitriev I et al. Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res 2002; 62: 1266–1270.
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.
Ono HA, Le LP, Davydova JG, Gavrikova T, Yamamoto M . Noninvasive visualization of adenovirus replication with a fluorescent reporter in the E3 region. Cancer Res 2005; 65: 10154–10158.
Richard JC, Factor P, Ferkol T, Ponde DE, Zhou Z, Schuster DP . Repetitive imaging of reporter gene expression in the lung. Mol Imaging 2003; 2: 342–349.
Nanda D, de Jong M, Vogels R, Havenga M, Driesse M, Bakker W et al. Imaging expression of adenoviral HSV1-tk suicide gene transfer using the nucleoside analogue FIRU. Eur J Nucl Med Mol Imaging 2002; 29: 939–947.
Krasnykh VN, Mikheeva GV, Douglas JT, Curiel DT . Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism. J Virol 1996; 70: 6839–6846.
Buick RN, Pullano R, Trent JM . Comparative properties of five human ovarian adenocarcinoma cell lines. Cancer Res 1985; 45: 3668–3676.
Bauerschmitz GJ, Guse K, Kanerva A, Menzel A, Herrmann I, Desmond RA et al. Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells. Mol Ther 2006; 14: 164–174.
Kanerva A, Zinn KR, Peng KW, Ranki T, Kangasniemi L, Chaudhuri TR et al. Noninvasive dual modality in vivo monitoring of the persistence and potency of a tumor targeted conditionally replicating adenovirus. Gene Therapy 2005; 12: 87–94.
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.
Yotnda P, Zompeta C, Heslop HE, Andreeff M, Brenner MK, Marini F . Comparison of the efficiency of transduction of leukemic cells by fiber-modified adenoviruses. Hum Gene Therapy 2004; 15: 1229–1242.
Ranki T, Kanerva A, Ristimaki A, Hakkarainen T, Sarkioja M, Kangasniemi L et al. A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer. Gene Therapy 2007; 14: 58–67.
Suzuki K, Fueyo J, Krasnykh V, Reynolds PN, Curiel DT, Alemany R . A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. Clin Cancer Res 2001; 7: 120–126.
Acknowledgements
This study was supported by Helsinki Graduate School in Biotechnology and Molecular Biology, Emil Aaltonen Foundation, EU FP6 THERADPOX and APOTHERAPY, HUCH Research Funds (EVO), Sigrid Juselius Foundation, Academy of Finland, Finnish Cancer Society, University of Helsinki, Sohlberg Foundation, Instrumentarium Research Fund, the Finnish Oncology Association and Deutsche Forschungsgemeinschaft (DFG).
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Guse, K., Dias, J., Bauerschmitz, G. et al. Luciferase imaging for evaluation of oncolytic adenovirus replication in vivo. Gene Ther 14, 902–911 (2007). https://doi.org/10.1038/sj.gt.3302949
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DOI: https://doi.org/10.1038/sj.gt.3302949
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