Abstract
Interferon‐β gene therapy for cancer is the first such protocol developed in Japan. Here we describe the development process of our interferon‐β gene therapy from basic research to clinical application. Interestingly, the biological and biochemical characteristics of interferon‐β gene therapy through transfer of the interferon‐(gene into tumor cells by means of cationic liposomes differed from those of conventional interferon‐β protein therapy. Interferon‐β gene transfer could induce apoptosis in interferon‐β protein‐resistant tumor cells, such as glioma, melanoma, and renal cell carcinoma. Induction of apoptosis was related to the level of intracellular mRNA of interferon‐β, prolongation of the phos‐phorylation time of molecules in the interferon‐p signal transduc‐tion pathway, such as JAK1, Trk2, and STAT1, and activation of DNase γ. In our preclinical study we developed lyophilized cat‐ionic liposomes containing interferon‐β gene (gene drug) for clinical use and confirmed their safety. Thereafter, we performed a pilot clinical trial in patients with malignant glioma and confirmed the safety and effectiveness of this interferon‐β gene therapy. In this review we also comment on the status of gene therapy regulation in Japan. Interferon‐β gene therapy is expected to become widely available for clinical use in cancer patients, and this new strategy might be extended to molecular targeting therapy, or used in combination with cell therapy or other therapies.
References
- 1. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JR, Ringold GM, Danielson M. Lipofection: a highly efficient, lipid‐medi‐ated DNA‐transfection procedure. Proc Natl Acad Sci USA 1987; 84: 7413–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Felgner RL, Ringold GM. Cationic liposome‐mediated transfection. Nature 1989; 337: 387–8. [DOI] [PubMed] [Google Scholar]
- 3. Mizuno M, Yoshida J, Sugita K, Inoue I, Seo H, Hayashi Y, Koshizaka T, Yagi K. Growth inhibition of glioma cells transfected with the human β‐in‐terferon gene by liposomes coupled with a monoclonal antibody. Cancer Res 1990; 50: 7826–9. [PubMed] [Google Scholar]
- 4. Mizuno M, Yoshida J, Sugita K, Yagi K. Growth inhibition of glioma cells of different cell lines by human interferon‐(produced in the cells transfected with its gene by means of liposomes. J Clin Biochem. Nutr 1990; 9: 73–7. [Google Scholar]
- 5. Yoshida J, Mizuno M, Yagi K. Secretion of human β‐interferon into the cystic fluid of glioma transfected with the interferon gene. J Clin Biochem Nutr 1991; 11: 123–8. [Google Scholar]
- 6. Yoshida J, Mizuno M, Yagi K. Antitumor effect of endogenous human β‐in‐terferon on malignant glioma and augmentation of the effect by tumor necrosis factor‐a. J Clin Biochem. Nutr 1992; 12: 153–60. [Google Scholar]
- 7. Mizuno M, Yoshida J, Oyama H, Sugita K. Growth inhibition of glioma cells by liposome‐mediated cell transfection with tumor necrosis factor‐a gene. Its enhancement by prior B‐interferon treatment. Neurol Med Chir (Tokyo) 1992; 32: 873–6. [DOI] [PubMed] [Google Scholar]
- 8. Yagi K, Noda H, Kurono M, Ohishi N. Efficient gene transfer with less cytotoxicity by means of cationic multilamellar liposomes. Biochem Biophys Res Commun 1993; 196: 1042–8. [DOI] [PubMed] [Google Scholar]
- 9. Shin N, Pardridge WM. Noninvasive gene targeting to the brain. Proc Natl Acad Sci USA 2000; 97: 7567–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Mizuno M, Yoshida J. Improvement of transduction efficiency of recombi nant adeno‐associated virus vector by entrapment in multilamellar liposomes. Jpn J Cancer Res 1998; 89: 352–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Natsume A, Mizuno M, Ryuke Y, Yoshida J. Cationic liposome conjugation to recombinant adenoviral vector reduces viral antigenicity. Jpn J Cancer Res 2000; 91: 363–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Mizuno M, Ryuke Y, Yoshida J. Cationic liposomes conjugation to recombinant adenoviral vectors containing herpes simplex virus thymidine kinase gene followed by ganciclovir treatment reduces viral antigenicity and maintains antitumor activity in mouse subcutaneous glioma model. Cancer Gene Ther 2002; 9: 825–9. [DOI] [PubMed] [Google Scholar]
- 13. Miyakoshi J, Dobler KD, Allalunis‐Turner J, McKean JDS, Petruk K, Allen PBR, Aronyk KN, Weir B, Huyser‐Wierenga D, Fulton D, Urtasun RC, Day RS III. Absence of IFNA and IFNB genes from human malignant glioma cell lines and lack of correlation with cellular sensitivity to interferons. Cancer Res 1990; 50: 278–83. [PubMed] [Google Scholar]
- 14. James CD, Carlbom JHE, Nordenskjold M, Cavenee WK, Collins VP. Chromosome 9 deletion mapping reveals interferon β and interferon β‐1 gene deletion in human glial tumors. Cancer Res 1991; 51: 1684–8. [PubMed] [Google Scholar]
- 15. Larsson I, Landstrom LE, Lamer E, Lundgren E, Miorner H, Strannegard O. Interferon production in glia and glioma cell lines. Infect Immun 1978; 22: 786–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Nehashi K, Yoshida J, Wakabayashi T, Nagata M, Utsumi J, Naruse N, Sugita K. Growth inhibition of human glioma cells by superinduced human interferon‐β. Neurol Med Chir (Tokyo) 1995; 35: 719–22. [DOI] [PubMed] [Google Scholar]
- 17. Salazar AM, Levy HB, Ondra S, Kende M, Scherokman B, Brown D, Mena H, Martin N, Schwab K, Donovan D, Dougherty D, Pulliam M, Ippolito M, Graves M, Brown H, Ommaya A. Long‐term treatment of malignant gliomas with intramuscularly administered polyinosinic‐polycytidylic acid stabilized with polylysine and carboxymethylcellulose; an open pilot study. Neurosur gery 1996; 38: 1096–104. [PubMed] [Google Scholar]
- 18. Kaynor C, Xin M, Wakefield J, Barsoum J, Qin XQ. Direct evidence that IFN‐beta functions as a tumor‐suppression protein. J Interferon Cytokine Res 2002; 22: 1089–98. [DOI] [PubMed] [Google Scholar]
- 19. Hanson C, Koepf I, Weijdegard A, Stierner U. Sensitivity to extrinsically supplied interferon and the endogenous expression of interferon in melanoma cell lines. Melanoma Res 1999; 9: 451–6. [DOI] [PubMed] [Google Scholar]
- 20. Saito R, Mizuno M, Kumabe T, Yoshimoto T, Tanuma S, Yoshida J. Apop totic DNA endonuclease (DNase‐γ) gene transfer induces cell death accompanying DNA fragmentation in human glioma cells. J Neuro-Oncol 2004; 67: 273–80. [DOI] [PubMed] [Google Scholar]
- 21. Duguay D, Mercier F, Stagg J, Martineau D, Bramson J, Servant M, Lin R, Galipeau J, Hiscott J. In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors. Cancer Res 2002; 62: 5148–52. [PubMed] [Google Scholar]
- 22. Zhang F, Lu W, Dong Z. Tumor‐infiltrating macrophages are involved in suppressing growth and metastasis of human prostate cancer cells by IFN‐β gene therapy in nude mice. Clin Cancer Res 2002; 8: 2942–51. [PubMed] [Google Scholar]
- 23. Yoshida J, Mizuno M, Yoshida J, Mizuno M, Fujii M, Kajita Y, Nakahara N, Hatano M, Saito R, Nobayashi M, Wakabayashi T. Human gene therapy formalignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human β‐interferon gene using cationic liposomes. Hum Gene Ther 2004; 15: 77–86. [DOI] [PubMed] [Google Scholar]
- 24. Brown JL, Barsoum J, Qin XQ. CD4+ T helper cell‐independent antitumor response mediated by murine IFN‐β gene delivery in immunocompetent mice. J Interferon Cytokine Res 2002; 22: 719–28. [DOI] [PubMed] [Google Scholar]
- 25. Parmiani G, Colombo MP. Somatic gene therapy of human melanoma: pre clinical studies and early clinical trials. Melanoma Res 1995; 5: 295–301. [DOI] [PubMed] [Google Scholar]
- 26. Nabel GJ, Gordon D, Bishop DK, Nickoloff BJ, Yang Z‐Y, Aruga A, Cameron MJ, Nabel EG, Chang AE. Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA‐liposome complexes. Proc Natl Acad Sci USA 1996; 93: 15388–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Kageshida T, Mizuno M, Ono T, Matsumoto K, Saida T, Yoshida J. Growth inhibition of human malignant melanoma transfected with the human inter feron‐β gene by means of cationic liposomes. Melanoma Res 2001; 11: 337–42. [DOI] [PubMed] [Google Scholar]
- 28. Ryuke Y, Mizuno M, Natsume A, Suzuki O, Nobayashi M, Kageshita T, Matsumoto K, Saida T, Yoshida J. Growth inhibition of subcutaneous mouse melanoma and induction of natural killer cells by liposome‐mediated inter‐feron‐β gene therapy. Melanoma Res 2003; 13: 349–56. [DOI] [PubMed] [Google Scholar]
- 29. Aoki H, Mizuno M, Natsume A, Tsugawa T, Tsujimura K, Takahashi T, Yoshida J. Dendritic cells pulsed with tumor extract‐cationic liposomes complex increase the induction of cytotoxic T lymphocytes in mouse brain tumor. Cancer Immunol Immunother 2002; 50: 463–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Nakanishi H, Mizutani Y, Kawauchi A, Ukimura O, Shiraishi T, Hatano M, Mizuno M, Yoshida J, Miki T. Significant antitumoral activity of cationic multilamellar liposomes containing human IFN‐β gene against human renal cell carcinoma. Clin Cancer Res 2003; 9: 1129–35. [PubMed] [Google Scholar]