Skip to main content

Advertisement

Log in

Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modality treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumor therapy is promising as it can be delivered in situ and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. In this article, we summarize the laboratory and clinical work using viral, cell-based, and synthetic vectors, as well as other strategies focused on potentiate gene delivery. Although tangible results on patients’ survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. The enthusiasm of this progress needs to be tempered by the realistic assessment of the challenges needed to be overcome. Finally, as the field of gene delivery progresses, advances must be made in identifying genes and proteins key to the treatment of malignant gliomas. Due to the great heterogeneity of malignant glioma cells, only approaches combining different strategies may be ultimately successful in defeating this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Surawicz TS, Davis F, Freels S, Laws ER Jr, Menck HR (1998) Brain tumor survival: results from the National Cancer Data Base. J Neurooncol 40:151–160. doi:10.1023/A:1006091608586

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ (2003) Cancer statistics, 2003. CA Cancer J Clin 53(1):5–26. doi:10.3322/canjclin.53.1.5

    Article  PubMed  Google Scholar 

  3. Benveniste R, Germano IM (2003) Evaluation of factors predicting accurate resection of high-grade gliomas using frameless image-guided stereotactic guidance. Neurosurg Focus 14:1–4. doi:10.3171/foc.2003.14.2.6

    Article  Google Scholar 

  4. Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC et al (2008) ALA-Glioma Study Group. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62(3):564–576

    Article  PubMed  Google Scholar 

  5. CBTRUS (Central Brain Tumor Registry of the United States) (2005) Primary brain tumors in the United States: statistical report tables, 1998–2002. http://www.cbtrus.org/2005-2006/tables/2006.table 18-19.pdf

  6. Chiocca EA (2003) Gene therapy: a primer for neurosurgeons. Neurosurgery 53:364–373. doi:10.1227/01.NEU.0000073532.05714.2B

    Article  PubMed  Google Scholar 

  7. Blase RM, Anderson WF (1990) The ADA human gene therapy clinical protocol. Hum Gene Ther 1:327–329. doi:10.1089/hum.1990.1.3-327

    Article  Google Scholar 

  8. Mochizuki H, Yasuda T, Mouzdran MM (2008) Advances in gene therapy for movement disorders. Neurotherapeutics 5:260–269. doi:10.1016/j.nurt.2008.01.005

    Article  PubMed  CAS  Google Scholar 

  9. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenhaler A, Notarangelo L, Wintergerst U, Buckley R, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri P, Miniero R, Bordignon C, Roncarolo MG (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458. doi:10.1056/NEJMoa0805817

    Article  PubMed  CAS  Google Scholar 

  10. Izquierdo M, Martin V, de Felipe P, Izquierdo JM, Perez-Higueras A, Cortes ML, Paz JF, Isla A, Blazquez MG (1996) Human malignant brain tumor response to herpes simplex virus thymidine kinase (HSV/tk)/ganciclovir gene therapy. Gene Ther 3:491–495

    PubMed  CAS  Google Scholar 

  11. Ram Z, Culver KW, Oshiro EM, Viola JJ, DeVroom HL, Otto E, Long Z, Chiang Y, McGarritty GJ, Muul LM, Katz D, Blaese RM, Oldfield EH (1997) Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 3:1354–1361. doi:10.1038/nm1297-1354

    Article  PubMed  CAS  Google Scholar 

  12. Klatzmann D, Valery CA, Bensimon G, Marro B, Boyer O, Mokhtari K, Diquet B, Salzmann JL, Philippon J (1998) A phase I/II study of herpes simplex virus type I thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Hum Gene Ther 9:2595–2604. doi:10.1089/hum.1998.9.17-2595

    Article  PubMed  CAS  Google Scholar 

  13. Shand N, Wever B, Bernstein M, Borradori-gianella A, Long Z, Sorensen AG, Barbier N (1999) A phase 1–2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex virus thymidine kinase gene followed by ganciclovir. Hum Gene Ther 10:2325–2335. doi:10.1089/10430349950016979

    Article  PubMed  CAS  Google Scholar 

  14. Rainov NG (2000) A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11:2389–2401. doi:10.1089/104303400750038499

    Article  PubMed  CAS  Google Scholar 

  15. Sandmair AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, Hurskainen H, Tyynela K, Turunen M, Vanninen R, Lethtolainen P, Paljarvi L, Johansson R, Vpalahti M, Yia-Herttuala S (2000) Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther 11:2197–2205. doi:10.1089/104303400750035726

    Article  PubMed  CAS  Google Scholar 

  16. Trask TW, Trask RP, Aguilar-Cordova E, Shine HD, Wyde PR, Goodman JC, Hamilton WJ, Rojas-Martinez A, Chen SH, Woo SLC, Grossman RG (2000) Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with recurrent malignant brain tumors. Mol Ther 1:195–203. doi:10.1006/mthe.2000.0030

    Article  PubMed  CAS  Google Scholar 

  17. Germano IM, Fable J, Gultekin SH, Silvers A (2003) Adenovirus/herpes simplex virus simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 65:279–289. doi:10.1023/B:NEON.0000003657.95085.56

    Article  PubMed  Google Scholar 

  18. Prados MD, McDermott M, Chang SM, Wilson CB, Fick J, Culver KW, Van Gilder J, Keles GE, Spence A, Berger M (2003) Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial. J Neurooncol 65:269–278. doi:10.1023/B:NEON.0000003588.18644.9c

    Article  PubMed  Google Scholar 

  19. Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C (2003) Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther 7:851–858. doi:10.1016/S1525-0016(03)00100-X

    Article  PubMed  CAS  Google Scholar 

  20. Immonem A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R, Langford G, Murray N, Yia-Herttuala S (2004) Adv/HSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomized controlled study. Mol Ther 10:967–972. doi:10.1016/j.ymthe.2004.08.002

    Article  CAS  Google Scholar 

  21. Harsh GR, Deisboeck TS, Louis DN, Hilton J, Covin M, Silver JS, Qureshi NH, Kracher J, Finkelstein D, Chiocca EA, Hochberg FH (2000) Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene marking and neuropathological study. J Neurosurg 92:804–811

    PubMed  CAS  Google Scholar 

  22. Molten FL (1986) Tumor chemosensitivity conferred by inserted thymidine kinase genes: paradigm for a perspective cancer control strategy. Cancer Res 46:5276–5281

    Google Scholar 

  23. Namba H, Tagawa M, Iwadate Y et al (1998) Bystander effect: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 53:5274–5283

    Google Scholar 

  24. Floeth FW, Shand N, Bojar H, Prisack HB, Felsberg J, Neuen-Jacob E, Aulich A, Burger KJ, Bock WJ, Weber F (2001) Local inflammation and devascularization—in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-tk/GCV gene therapy in human malignant glioma. Cancer Gene Ther 8:843–851. doi:10.1038/sj.cgt.7700382

    Article  PubMed  CAS  Google Scholar 

  25. Lee J, Hampl M, Albert P, Fine H (2002) Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector. Neoplasia 4:312–323. doi:10.1038/sj.neo.7900245

    Article  PubMed  CAS  Google Scholar 

  26. Li H, Alonso-Vangeas M, Colicos MA, Jung SS, Lochmuller H, Sadikot AF, Snipes GJ, Seth P, Karpati G, Nalbantoglu J (1999) Intracerebral adenovirus-mediated p53 tumor suppressor gene therapy for experimental human glioma. Clin Cancer Res 5:637–642

    PubMed  CAS  Google Scholar 

  27. Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang MS, Berger S, NcDermott MW, Kuunwar SM, Junch LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WKA (2003) Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 21:2508–2518. doi:10.1200/JCO.2003.11.138

    Article  PubMed  CAS  Google Scholar 

  28. Shinuora N, Koike H, Furitu T, Hashimoto M, Asai A, Kirino T, Hamada H (2000) Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas: implication for gene therapy. Hum Gene Ther 11:1123–1137. doi:10.1089/10430340050015185

    Article  Google Scholar 

  29. Iwadate Y, Inoue M, Saegusa T, Tokusumi Y, Kinoh H, Hasegawa M, Tagawa M, Yamamura A, Shimada H (2005) Recombinant sendai virus vector induces complete remission of established brain tumors through efficient interleukin-2 gene transfer in vaccinated rats. Clin Cancer Res 11:3821–3827. doi:10.1158/1078-0432.CCR-04-1485

    Article  PubMed  CAS  Google Scholar 

  30. Liu Y, Ehtesham M, Samoto K, Wheeler CJ, Thompson RC, Villarreal LP, Black KL, Yu JS (2002) In situ adenoviral interleukin-12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma. Cancer Gene Ther 9:9–15. doi:10.1038/sj.cgt.7700399

    Article  PubMed  CAS  Google Scholar 

  31. Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM (2000) Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci USA 97:2208–2213. doi:10.1073/pnas.040557897

    Article  PubMed  CAS  Google Scholar 

  32. Daga A, Orreng AM, Gangemi RMR, Marubbi D, Perera M, Comes A, Ferrini S, Corte G (2007) Glioma immunotherapy by IL-21 gene-modified cells or by recombinant IL-21 involves antibody responses. Int J Cancer 121:1756–1763. doi:10.1002/ijc.22901

    Article  PubMed  CAS  Google Scholar 

  33. Ambar BB, Frei K, Malipiero U, Morelli AE, Castro MG, Lowenstein PR, Fontana A (1999) Treatment of experimental glioma by administration of adenoviral vectors expressing Fas ligand. Hum Gene Ther 10:1641–1648. doi:10.1089/10430349950017644

    Article  PubMed  CAS  Google Scholar 

  34. Maleniak TC, Darling JL, Lowenstein PR, Castro MG (2001) Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU. Cancer Gene Ther 8:589–598. doi:10.1038/sj.cgt.7700348

    Article  PubMed  CAS  Google Scholar 

  35. Chiocca EA, Smith KM, McKinney B, Palmer CA, Rosenfeld S, Lillehei K, Hamilton A, DeMasters BK, Judy K, Kirm D (2008) A phase I trial of Ad.hIFN-beta gene therapy for glioma. Mol Ther 16:618–626. doi:10.1038/sj.mt.6300396

    Article  PubMed  CAS  Google Scholar 

  36. Ehtesham M, Kabos P, Gutierrez MA, Chung NH, Griffith TS, Black KL, Yu JS (2002) Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 62(24):7170–7174

    PubMed  CAS  Google Scholar 

  37. Arnhold S, Hilgers M, Lenartz D, Sekova I, Kochanek S, Voges J et al (2003) Neural precursor cells as carriers for a gene therapeutical approach in tumor therapy. Cell Transplant 12(8):827–837

    PubMed  CAS  Google Scholar 

  38. Ehtesham M, Samoto K, Kabos P, Acosta FL, Gutierrez MAR, Black KL, Yu JS (2002) Treatment of intracranial glioma with in situ interferon gamma and tumor necrosis factor alpha gene transfer. Cancer Gene Ther 9:925–934. doi:10.1038/sj.cgt.7700516

    Article  PubMed  CAS  Google Scholar 

  39. Benveniste RJ, Keller G, Germano I (2005) Embryonic stem cell-derived astrocytes expressing drug-inducible transgenes: differentiation and transplantation into the mouse brain. J Neurosurg 103(1):115–123

    Article  PubMed  CAS  Google Scholar 

  40. Lee J, Elkahloun AG, Messina SA, Ferrari N, Xi D, Smith CL (2003) Cellular, genetic characterization of human adult bone marrow-derived neural stem-cell like cells: a potential antiglioma cellular vector. Cancer Res 63:8877–8889

    PubMed  CAS  Google Scholar 

  41. Nakamura K, Ito Y, Kawano Y, Kurozomi K, Kobune M, tsuda H et al (2004) Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 11:1155–1164. doi:10.1038/sj.gt.3302276

    Article  PubMed  CAS  Google Scholar 

  42. Moore Xl, Lu J, Sun L, Zhu CJ, Tan P, Wong MC (2004) Endothelial progenitor cells ‘homing’ specificity to brain tumors. Gene Ther 11:811–818. doi:10.1038/sj.gt.3302151

    Article  PubMed  CAS  Google Scholar 

  43. Glick RP, Lichtor T, Panchal P, Mahendra A, Cohen EP (2003) Treatment with allogeneic interleukin-2 secreting fibroblasts protects against the development of malignant brain tumors. J Neurooncol 64:139–146

    PubMed  Google Scholar 

  44. Okada H, Lieberman FS, Edington HD, Witham TF, Wargo MJ, Cai Q, Elder EH, Whiteside TL, Schold C, Pollack IF (2003) Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of recurrent glioblastoma: preliminary observations in a patient with a favorable response to therapy. J Neurooncol 64:13–20

    PubMed  Google Scholar 

  45. Okada H, Lieberman FS, Walter KA, Lunsford LD, Kondziolka DS, Bejjani GK, Hamilton RL, Torres-Trejo A, Kalinski P, Cai Q, Mabold JL, Edington HD, Butterfield LH, Whiteside TL, Potter DM, Schold SC, Pollack IF (2007) Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J Transl Med 5:67–77. doi:10.1186/1479-5876-5-67

    Article  PubMed  CAS  Google Scholar 

  46. Germano IM, Uzzaman M, Keller G (2008) Gene delivery by embryonic stem cells for malignant gliomas. Cancer Biol Ther 7:1341–1347

    PubMed  CAS  Google Scholar 

  47. Jandial R, Singec I, Ames CP, Snyder EY (2008) Genetic modification of neural stem cells. Mol Ther 16(3):450–457. doi:10.1038/sj.mt.6300402

    Article  PubMed  CAS  Google Scholar 

  48. Uzzaman M, Benveniste R, Keller G, Germano IM (2005) Embryonic stem cell-derived astrocytes: novel gene therapy vector for brain tumors. Neurosurg Focus 19(3):E6–E16. doi:10.3171/foc.2005.19.3.7

    Article  PubMed  Google Scholar 

  49. Germano IM, Uzzaman M, Benveniste RJ, Zaurova M, Keller G (2006) Apoptosis in human glioblastoma cells produced using embryonic stem cell-derived astrocytes expressing tumor necrosis factor-related apoptosis-inducing ligand. J Neurosurg 105(1):88–95. doi:10.3171/jns.2006.105.1.88

    Article  PubMed  CAS  Google Scholar 

  50. Uzzaman M, Keller G, Germano I (2008) In vivo gene delivery by embryonic stem cell-derived astrocytes for malignant gliomas. Neuro-oncology. doi:10.1215/15228517-2008-056

    PubMed  Google Scholar 

  51. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecit G, Dembinski J, Andreef M, Lang FF (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318

    PubMed  CAS  Google Scholar 

  52. Barresi V, Belluardo N, Sipione S, Mudo G, Cattaneo E, Condorelli DF (2003) Transplantation of prodrug-converting neuronal progenitor cells for brain tumor therapy. Cancer Gene Ther 10:396–402. doi:10.1038/sj.cgt.7700580

    Article  PubMed  CAS  Google Scholar 

  53. Uhl M, Weiler M, Wick W, Jacobs AH, Weller M, Herrlinger U (2005) Migratory neural stem cells for improved thymidine kinase-based gene therapy of malignant gliomas. Biochem Biophys Res Commun 328:125–129. doi:10.1016/j.bbrc.2004.12.164

    Article  PubMed  CAS  Google Scholar 

  54. Herrlinger U, Woiciechowski C, Sena-Estevez M, Aboody KS, Jacobs AH, Rainov NG (2000) Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Mol Ther 1:347–357. doi:10.1006/mthe.2000.0046

    Article  PubMed  CAS  Google Scholar 

  55. Kingsley JD, Dou H, Morehead J, Robinow B, Gendelman HE (2006) Nanotechnology: a focus on nanoparticles as a drug delivery system. J Neuroimmune Pharmacol 1:340–350. doi:10.1007/s11481-006-9032-4

    Article  PubMed  Google Scholar 

  56. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JR, Ringold GM, Danielson M (1987) Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA 84:7413–7414. doi:10.1073/pnas.84.21.7413

    Article  PubMed  CAS  Google Scholar 

  57. Yoshida J, Mizuno M, Fujii M, Kajita Y, Nakahara N, Hatano M (2004) Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytomas) by in vivo transduction with human interferon beta gene using cationic liposomes. Hum Gene Ther 15:77–86. doi:10.1089/10430340460732472

    Article  PubMed  CAS  Google Scholar 

  58. Mabuchi E, Shimizu K, Miyao Y, Kaneda Y, Kishima H, Tamura M, Ikenaka K, Hayakawa T (1997) Gene delivery by HVJ-liposome in the experimental gene therapy of murine glioma. Gene Ther 4:768–772. doi:10.1038/sj.gt.3300478

    Article  PubMed  CAS  Google Scholar 

  59. Voges J, Reszka R, Grossmann A, Dittmar C, Richter R, Garlip G, Kracht L, Coenen HH, Sturm V, Wienhard K, Heiss WD, Jacobs A (2003) Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma. Ann Neurol 54:479–487. doi:10.1002/ana.10688

    Article  PubMed  CAS  Google Scholar 

  60. Defougerolles AR (2008) Delivery vehicles for small interfering RNA in vivo. Hum Gene Ther 19:125–132. doi:10.1089/hum.2008.928

    Article  CAS  Google Scholar 

  61. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM (1991) Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252:854–856. doi:10.1126/science.1851332

    Article  PubMed  CAS  Google Scholar 

  62. Chiocca EA (2002) Oncolytic viruses. Nature 2:938–951

    Google Scholar 

  63. Wang WJ, Tai CK, Kasahara N, Chen TC (2003) Highly efficient and tumor-restricted gene transfer to malignant gliomas by replication-competent retroviral vectors. Hum Gene Ther 14:117–127. doi:10.1089/104303403321070810

    Article  PubMed  CAS  Google Scholar 

  64. Lawler SE, Peruzzi PP, Chiocca EA (2006) Genetic strategies for brain tumor therapy. Cancer Gene Ther 13:225–233. doi:10.1038/sj.cgt.7700886

    Article  PubMed  CAS  Google Scholar 

  65. Lamfers M, Grill J, Dirven C, van Beuceschem VW, Georger B, Van Der Berg J (2002) Potential of the conditionally replicative adenovirus Ad5-D24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy. Cancer Res 62:5736–5742

    PubMed  CAS  Google Scholar 

  66. Hutterer M, Gunsilius E, Stockhammer G (2006) Molecular therapies for malignant gliomas. Wien Med Wochenschr 12:351–363. doi:10.1007/s10354-006-0308-3

    Article  Google Scholar 

  67. Enderlin M, Kleinman EV, Struyf F, Buracchi C, Vecchi A, Kinscherf R, Kiessling F, Paschek S, Sozzani S, Rommelaere J, Cornelis JJ, Van Damme J, Dinsart C (2009) TNF-alpha and the IFN-beta-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma. Cancer Gene Ther 16(2):149–160. doi:10.1038/cgt.2008.62

    Article  PubMed  CAS  Google Scholar 

  68. Raj K, Ogston P, Beard P (2001) Virus-mediated killing of cells that lack p53 activity. Nature 412:914–917. doi:10.1038/35091082

    Article  PubMed  CAS  Google Scholar 

  69. Mizuno M, Yoshida J, Colosi P, Kurtzman G (1998) Adeno-associated virus vector containing the herpes simplex virus thymidine kinase gene causes complete regression of intracerebrally implantable human glioma in mice, in conjunction with ganciclovir administration. Jpn J Cancer Res 89:76–80

    PubMed  CAS  Google Scholar 

  70. Harding T, Lalani A, Roberts BN, Yendluri S, Luan B, Koprivnikar K, Gonzalez-Edick M, Huan-Tu G, Musterer R, VanRoey MJ, Ozawa T, LeCouter RA, Deen D, Dickinson PJ, Jooss K (2006) AAV serotype 8-mediated gene delivery of a soluble VEGF receptor to the treatment of glioblastoma. Mol Ther J Am Soc Gene Ther 13:956–966

    CAS  Google Scholar 

  71. Ma H-I, Lin S-Z, Chiang Y-H, li L, Chen S-L, Tsao Y-P, Xiao X (2002) Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associated viral (AAV) vector. Gene Ther 9:2–11

    Article  PubMed  CAS  Google Scholar 

  72. Maguire C, Meijer D, LeRoy S, Tierny LA, Broekman MLD, Costa F, Breakefield XO, Stemmer-Rachaminov A, Sena-Esteves M (2008) Preventing growth of rain tumors by creating a zone resistance. Mol Ther 16:1695–1702

    Article  PubMed  CAS  Google Scholar 

  73. Yanamandra N, Kondraganti S, Gondi C, Gujrati M, Olivero W, Dinh D, Rao J (2005) Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line. Int J Cancer 115:998–1005. doi:10.1002/ijc.20965

    Article  PubMed  CAS  Google Scholar 

  74. Yoshida J, Mizuno M, Nakahara N, Colosi P (2002) Antitumor effect of an adeno-associated virus vector containing the human interferon-beta gene on experimental intracranial glioma. Jpn J Cancer Res 93:223–228

    PubMed  CAS  Google Scholar 

  75. Foust K, Nurre E, Montgomery CL, Hermandez A, Chan C, Kaspar BK (2009) Intravascular AAV9 preferentially targets neonatal neurons and adults astrocytes. Nat Biotechnol 27:59–65. doi:10.1038/nbt.1515

    Article  PubMed  CAS  Google Scholar 

  76. Alexander BL, Ali RR, Alton EW, Bainbridge JW, Brown S, Cheng SH (2007) Progress and prospect. Gene therapy clinical trials. Gene Ther 14:147–1439. doi:10.1038/sj.gt.3303001

    Google Scholar 

  77. Zarnitsyn VG, Kamaev PP, Prausnitz MR (2007) Ultrasound-enhanced chemotherapy and gene delivery for glioma cells. Technol Cancer Res Treat 6:433–442

    PubMed  CAS  Google Scholar 

  78. Benedetti S, Bruzzone SG, Pollo B, DiMeco F, Magrassi L, Pirola B, Cirenei N, Colombo MP, Finocchiaro G (1999) Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin-4 gene. Cancer Res 59:645–652

    PubMed  CAS  Google Scholar 

  79. Palu G, Cavaggioni A, Calvi P, Franchin E, Pizzato M, Boschetto R, Parolini C, Chilosi M, Ferrini S, Zanusso A, Colombo F (1999) Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine gene: a pilot study in humans. Gene Ther 6:330–337. doi:10.1038/sj.gt.3300805

    Article  PubMed  CAS  Google Scholar 

  80. Colombo F, Barzon L, Franchin E, Pacenti M, Pinna V, Danieli D, Zannusso M, Palu G (2005) Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther 12:835–848. doi:10.1038/sj.cgt.7700851

    Article  PubMed  CAS  Google Scholar 

  81. Ali S, Curtin JF, Zinger JM, Xiong W, King GD, Barcia C, Liu C, Puntel M, Goverdhana S, Lowenstein PR, Castro MG (2004) Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFLt3L): treatment with hsFLt3L inhibits intracranial glioma progression. Mol Ther 10:1071–1084. doi:10.1016/j.ymthe.2004.08.025

    Article  PubMed  CAS  Google Scholar 

  82. Ali S, King GD, Curtin JF, Candolfi M, Xiong W, Lui C, Puntel M, Cheng Q, Prieto J, Ribas A, Kupiec-Weglinski J, van Rooijen N, Lassmann H, Lowenstein PR, Castro MG (2005) Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. Cancer Res 65:7194–7204. doi:10.1158/0008-5472.CAN-04-3434

    Article  PubMed  CAS  Google Scholar 

  83. King GD, Muhammad AKMG, Xiong W, Kroeger KM, Puntel M, Larocque D, Palmer D, Ng P, Lowenstein PR, Castro MG (2008) High-capacity adenovirus vector-mediated anti-glioma gene therapy in the presence of systemic antiadenovirus immunity. J Virol 82:4680–4684. doi:10.1128/JVI.00232-08

    Article  PubMed  CAS  Google Scholar 

  84. Fulci G, Breymann L, Gianni D, Kurozomi K, Rhee SS, Yu J et al (2006) Cyclophospahamide enhances glioma virotherapy by inhibiting innate immune responses. Proc Natl Acad Sci USA 103:12873–12878. doi:10.1073/pnas.0605496103

    Article  PubMed  CAS  Google Scholar 

  85. Fisher PB (2005) Is mda7/IL24 a “magic bullet” for cancer? Cancer Res 65:22–35. doi:10.1158/0008-5472.CAN-05-3127

    Article  CAS  Google Scholar 

  86. Cho HI, Kim HJ, Oh ST, Kim TG (2003) In vitro induction of carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte by dentridic cells transduced with recombinant adenoviruses. Vaccine 22:224–228

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isabelle M. Germano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Germano, I.M., Binello, E. Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside. J Neurooncol 93, 79–87 (2009). https://doi.org/10.1007/s11060-009-9869-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-009-9869-5

Keywords

Navigation