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A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

Cancer Gene Therapy volume 17, pages 837–843 (2010)Cite this article

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Abstract

The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 1010 to 2 × 1012 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 1012 vp per patient.

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References

  1. Parkin DM, Bray F, Ferlay J, Pisani P . Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108.

    Article  Google Scholar 

  2. El-Serag HB, Mason AC . Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340: 745–750.

    Article  CAS  Google Scholar 

  3. El-Serag HB, Marrero JA, Rudolph L, Reddy KR . Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134: 1752–1763.

    Article  Google Scholar 

  4. Bruix J, Sherman M . Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208–1236.

    Article  Google Scholar 

  5. Llovet JM, Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698–711.

    Article  Google Scholar 

  6. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–390.

    Article  CAS  Google Scholar 

  7. Avila MA, Berasain C, Sangro B, Prieto J . New therapies for hepatocellular carcinoma. Oncogene 2006; 25: 3866–3884.

    Article  CAS  Google Scholar 

  8. Mohr L, Geissler M, Blum HE . Gene therapy for malignant liver disease. Expert Opin Biol Ther 2002; 2: 163–175.

    Article  CAS  Google Scholar 

  9. Fillat C, Carrio M, Cascante A, Sangro B . Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther 2003; 3: 13–26.

    Article  CAS  Google Scholar 

  10. Shen Y, Nemunaitis J . Herpes simplex virus 1 (HSV-1) for cancer treatment. Cancer Gene Ther 2006; 13: 975–992.

    Article  CAS  Google Scholar 

  11. Vassaux G, Martin-Duque P . Use of suicide genes for cancer gene therapy: study of the different approaches. Expert Opin Biol Ther 2004; 4: 519–530.

    Article  CAS  Google Scholar 

  12. Matthews T, Boehme R . Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis 1998; 10 (Suppl 3): S490–S494.

    Google Scholar 

  13. Moolten FL . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986; 46: 5276–5281.

    CAS  PubMed  Google Scholar 

  14. Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53: 5274–5283.

    CAS  PubMed  Google Scholar 

  15. Kianmanesh AR, Perrin H, Panis Y, Fabre M, Nagy HJ, Houssin D et al. A “distant” bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Hum Gene Ther 1997; 8: 1807–1814.

    Article  CAS  Google Scholar 

  16. Kuriyama S, Kikukawa M, Masui K, Okuda H, Nakatani T, Akahane T et al. Cancer gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo. Int J Cancer 1999; 83: 374–380.

    Article  CAS  Google Scholar 

  17. Qian C, Idoate M, Bilbao R, Sangro B, Bruña O, Vázquez J et al. Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther 1997; 8: 349–358.

    Article  CAS  Google Scholar 

  18. Bilbao R, Gérolami R, Bralet MP, Qian C, Tran PL, Tennant B et al. Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal model. Cancer Gene Ther 2000; 7: 657–662.

    Article  CAS  Google Scholar 

  19. Qian C, Bilbao R, Bruna O, Prieto J . Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase. Hepatology 1995; 22: 118–123.

    CAS  PubMed  Google Scholar 

  20. Herraiz M, Beraza N, Solano A, Sangro B, Montoya J, Qian C et al. Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion. Hum Gene Ther 2003; 14: 463–472.

    Article  CAS  Google Scholar 

  21. Su H, Lu R, Chang JC, Kan YW . Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice. Proc Natl Acad Sci USA 1997; 94: 13891–13896.

    Article  CAS  Google Scholar 

  22. Penuelas I, Mazzolini G, Boán JF, Sangro B, Martí-Climent J, Ruiz M et al. Positron emission tomography imaging of adenoviral-mediated transgene expression in liver cancer patients. Gastroenterology 2005; 128: 1787–1795.

    Article  CAS  Google Scholar 

  23. WHO: Handbook of Reporting Results of Cancer Treatment 1979. Publication No. 48. WHO: Geneva, Switzerland.

  24. National Cancer Institute: Guidelines for the Reporting of Adverse Drug Reactions. National Cancer Institute: Bethesda, MD, 1990, pp 1–80.

  25. Karch FE, Lasagna L . Adverse drug reactions. A critical review. JAMA 1975; 234: 1236–1241.

    Article  CAS  Google Scholar 

  26. Penuelas I, Boán JF, Martí-Climent JM, Barajas MA, Narvaiza I, Satyamurthy N et al. A fully automated one pot synthesis of 9-(4-[18F]fluoro-3-hydroxymethylbutyl) guanine for gene therapy studies. Mol Imaging Biol 2002; 4: 415–424.

    Article  Google Scholar 

  27. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421–430.

    Article  CAS  Google Scholar 

  28. Wilson JM . Adenoviruses as gene-delivery vehicles. N Engl J Med 1996; 334: 1185–1187.

    Article  CAS  Google Scholar 

  29. Drozdzik M, Qian C, Xie X, Peng D, Bilbao R, Mazzolini G et al. Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma. J Hepatol 2000; 32: 279–286.

    Article  CAS  Google Scholar 

  30. Li N, Zhou J, Weng D, Zhang C, Li L, Wang B et al. Adjuvant adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of liver transplantation in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2007; 13: 5847–5854.

    Article  CAS  Google Scholar 

  31. Sung MW, Yeh HC, Thung SN, Schwartz ME, Mandeli JP, Chen SH et al. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial. Mol Ther 2001; 4: 182–191.

    Article  CAS  Google Scholar 

  32. Penuelas I, Haberkorn U, Yaghoubi S, Gambhir SS . Gene therapy imaging in patients for oncological applications. Eur J Nucl Med Mol Imaging 2005; 32 (Suppl 2): S384–S403.

    Article  Google Scholar 

  33. Sangro B, Qian C, Ruiz J, Prieto J . Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field. Mol Imaging Biol 2002; 4: 27–33.

    Article  Google Scholar 

  34. Ido A, Uto H, Moriuchi A, Nagata K, Onaga Y, Onaga M et al. Gene therapy targeting for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter. Cancer Res 2001; 61: 3016–3021.

    CAS  PubMed  Google Scholar 

  35. Teh BS, Aguilar-Cordova E, Kernen K, Chou CC, Shalev M, Vlachaki MT et al. Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--a preliminary report. Int J Radiat Oncol Biol Phys 2001; 51: 605–613.

    Article  CAS  Google Scholar 

  36. Stefani AL, Barzon L, Castagliuolo I, Guido M, Pacenti M, Parolin C et al. Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma. J Hepatol 2005; 42: 728–735.

    Article  CAS  Google Scholar 

  37. Torimura T, Ueno T, Kin M, Taniguchi E, Nakamura T, Inoue K et al. Gene transfer of kringle 1-5 suppresses tumor development and improves prognosis of mice with hepatocellular carcinoma. Gastroenterology 2006; 130: 1301–1310.

    Article  CAS  Google Scholar 

  38. Shinozaki K, Suominen E, Carrick F, Sauter B, Kähäri VM, Lieber A et al. Efficient infection of tumor endothelial cells by a capsid-modified adenovirus. Gene Ther 2006; 13: 52–59.

    Article  CAS  Google Scholar 

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Acknowledgements

CIBERehd is funded by the Instituto de Salud Carlos III. This work has been funded in part by Fundación Areces and Accion Transversal contra el Cancer. We thank Maria Eugenia Cornet, Maria del Mar Municio, Viñas Andrés and Elena del Corral for their work in trial monitoring.

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Author notes

  1. G Mazzolini

    Present address: 7Current address: Gene Therapy Laboratory, Liver Unit. School of Medicine. Austral University. Av. Presidente Perón 1500, (B1629ODT) Derqui-Pilar, Buenos Aires, Argentina.,

Authors and Affiliations

  1. Liver Unit, Clínica Universitaria, Pamplona, Spain

    B Sangro, G Mazzolini, M Ruiz, J Quiroga, I Herrero & J Prieto

  2. Centro de Investigacion Biomedica en Red de Enfermedades Hepáticas y Digestivas. (CIBERehd), Pamplona, Spain

    B Sangro, J Quiroga, I Herrero & J Prieto

  3. Division of Gene Therapy, Center for Biomedical Research, Pamplona, Spain

    J Ruiz, C Qian & C Olagüe

  4. Department of Radiology, Clinica Universitaria, Pamplona, Spain

    A Benito & J Larrache

  5. Department of Nuclear Medicine, Clinica Universitaria, Pamplona, Spain

    J Boan & I Peñuelas

  6. Department of Pharmacology, Clinica Universitaria, Pamplona, Spain

    B Sádaba

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  1. B Sangro
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Correspondence to B Sangro.

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Sangro, B., Mazzolini, G., Ruiz, M. et al. A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma. Cancer Gene Ther 17, 837–843 (2010). https://doi.org/10.1038/cgt.2010.40

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  • DOI: https://doi.org/10.1038/cgt.2010.40

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