Skip to main content
SpringerLink
Log in

Adenovirus Mediated Gene Therapy in a Glioblastoma Vaccine Model; Specific Antitumor Immunity and Abrogation of Immunosuppression

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

Abstract

Clinical trials are being performed using tumor genetically engineered to produce cytokines as a vaccine. The design of such a vaccine may be made more effective by further study using in-vitro as well as in-vivo models. We studied an in-vitro tumor ‘vaccine’ model in glioblastoma. We have demonstrated high efficiency transfection of the Interleukin-2 (IL-2) gene into glioblastoma cell lines using adenoviral vectors. Glioblastoma cell lines transduced with this vector could produce high levels of IL-2 for up to 2 weeks, long enough to elicit an antitumor immune response. We studied tumor/effector cell interactions using cytotoxicity assays coupled with flow cytometric analysis. Activation of CD8+ and expansion of CD3+/CD16+ effector cell subpopulations were observed, suggesting the generation of a specific anti-tumor response and the potential for systemic immunity. We demonstrated that glioblastoma produce immunosuppressive factors which reduce the antitumor response by peripheral blood effector cells. These immunosuppressive factors could be neutralized to improve antitumor response. A better understanding of tumor/effector cell interactions may improve the design of gene therapy trials.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Polednak AP, Flannery JT: Brain, other central nervous system, and eye cancer. Cancer 75(1 Suppl): 330–337, 1995

    Google Scholar 

  2. Tepper R, Pattengale P, Leder P: Murine interleukin-4 displays potent antitumor activity in-vivo. Cell 57: 503–512, 1989

    Google Scholar 

  3. Roth J, Cristiano R: Gene therapy for cancer: What have we done and where are we going? J Natl Cancer Inst 89(1): 21–39, 1997

    Google Scholar 

  4. Leimig T, Brenner M, Ramsey J, Vanin E, Blaese M, Dilloo D: High-efficiency transduction of freshly isolated human tumor cells using adenoviral interleukin-2 vectors. Hum Gene Ther 7: 1233–1239, 1996

    Google Scholar 

  5. Stratford-Perricaudet L, Makeh I, Perricaudet M, Briand P: Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest 90: 626–630, 1992

    Google Scholar 

  6. Brooks WH, Netsky MG, Normansell DE, Horwitz DA: Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor. J Exp Med 136(6): 631–1647, 1972

    Google Scholar 

  7. Roszman T, Elliott L, Brooks W: Modulation of T-cell function by gliomas. Immunol Today 12: 370–374, 1991

    Google Scholar 

  8. Bodmer S, Strommer K, Frei K, Siepl C, De Tribolet N, Heid I, Fontana A. Immunosuppression and transforming growth factor-β in glioblastoma. J Immunol 143(10): 3222–3229, 1989

    Google Scholar 

  9. Jachimczak P, Bogdahn U, Schneider J, Behl C, Meixensberger J, Apfel R, Dörries R, Schlingensiepen KH, Brysch W: The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78: 944–951, 1993

    Google Scholar 

  10. Fakhrai H, Dorigo O, Shawler DL, Lin H, Mercola D, Black KL, Royston J, Sobol RE: Eradication of established intracranial rat gliomas by transforming growth factor β antisense gene therapy. Proc Natl Acad Sci USA 93(7): 2909–2914, 1996

    Google Scholar 

  11. Kuratsu J-I, Estes JE, Yokota S, Mahaley MS Jr, Gillespie GY: Growth factors derived from a human malignant glioma cell line, U-251MG. J Neuro-onc 7: 225–235, 1989

    Google Scholar 

  12. Brenner MK, Funrman WL, Santana VM, Bowman L, Meyer W: Phase 1 study of cytokine-gene modified autologous neuroblastoma cells for treatment of relapsed/refractory neuroblastoma. Hum Gene Ther 3: 437–447, 1992

    Google Scholar 

  13. Sanes J, Rubenstein J, Nicolas J: Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J 5(12): 3133–3142, 1986

    Google Scholar 

  14. Myers Kazimer R, Whisler R, Stephens R, Pearl D, Yates J: Sensitivity of glioma and fetal brain cell lines to natural killer cytolysis in a monolayer assay. J Neuro-Onc 7: 145–152, 1989

    Google Scholar 

  15. Simms P, Ellis T: Utility of flow cytometric detection of CD69 expression as a rapid method for determining poly-and oligoclonal lymphocyte activation. Clin Diagn Lab Immunol 3(3): 301–304, 1996

    Google Scholar 

  16. Miltenyi S, Müller W, Weichel W, Radbruch A: High gradient magnetic separation with MACS. Cytometry 11: 231–238, 1990

    Google Scholar 

  17. Li Q, Kay M, Finegold M, Stratford-Perricaudet L, Woo S: Assessment of recombinant adenoviral vectors for hepatic gene therapy. Hum Gene Ther 4: 403–409, 1993

    Google Scholar 

  18. Rill DR, Buschle M, Foreman NK, Bartholomew C, Moen RC, Santana VM, Ihle JN, Brenner MK: Retrovirus mediated gene transfer as an approach to analyze neuroblastoma relapse after autologous bone marrow transplantation. Hum Gene Ther 3: 129–136, 1992

    Google Scholar 

  19. Le Gal La Salle G, Robert JJ, Berrard S, Ridoux V, Stratford-Perricaudet LD, Perricaudet M, Mallet J: An adenovirus vector for gene transfer into neurons and glia in the brain. Science 259: 988–990, 1993

    Google Scholar 

  20. Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL: Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in-vivo. Proc Natl Acad Sci USA 91(8): 3054–3057, 1994

    Google Scholar 

  21. Cordier L, Duffour MT, Sabourin JC, Lee MG, Cabannes J, Ragot T, Perricaudet M, Haddada H: Complete recovery of mice from a pre-established tumor by direct intratumoral delivery of an adenovirus vector harboring the murine IL-2 gene. Gene Therapy 2(1): 16–21, 1995

    Google Scholar 

  22. Bich-Thuy L, Dukovich M, Peffer NJ, Fauci A, Kehrl J, Greene W: Direct activation of human resting T cells by IL-2: the role of an IL-2 receptor distinct from the TAC protein. J Immunol 139: 1550–1556, 1987

    Google Scholar 

  23. Sobol RE, Fakhrai H, Shawler D, Gjerset R, Dorigo O, Carson C, Khaleghi T, Koziol J, Shiftan TA, Royston I: Interleukin-2 gene therapy in a patient with glioblastoma. Gene Therapy 2(2): 164–167, 1995

    Google Scholar 

  24. Tsurushima H, Liu SQ, Tsuboi K, Yoshii Y, Nose T, Ohno T: Induction of human autologous cytotoxic T lymphocytes against minced tissues of glioblastoma multiforme. J Neurosurg 84(2): 258–263, 1996

    Google Scholar 

  25. Takeda K, Dennert G: Demonstration of MHC class I-specific cytolytic activity in IL-2-activated NK1+CD3+cells and evidence of usage of T and NK cell receptors. Transplantation 58(4): 496–504, 1994

    Google Scholar 

  26. Jachimczak P, Schwulera U, Bogdahn U: In-vitro studies of cytokine-mediated interactions between malignant glioma and autologous peripheral blood mononuclear cells. J Neurosurg 81(4): 579–586, 1994

    Google Scholar 

  27. Wrann M, Bodmer S, De Martin R, Siepl C, Hofer-Warbinek R, Frei K, Hofer E, Fontana A: T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. EMBO J 6(6): 1633–1636, 1987

    Google Scholar 

  28. Panek RB, Lee YJ, Benveniste EN: TGF-beta suppression of IFN-gamma-induced class II MHC gene expression does not involve inhibition of phosphorylation of JAK1, JAK2, or signal transducers and activators of transcription, or modification of IFN-gamma enhanced factor X expression. J Immunol 154(2): 610–619, 1995

    Google Scholar 

  29. Ranges GE, Figari IS, Espevik T, Palladino MA Jr: Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med 166(4): 991–998, 1987

    Google Scholar 

  30. Elliott LH, Brooks WH, Roszman TL: Suppression of high affinity IL-2 receptors on mitogen activated lymphocytes by glioma-derived suppressor factor. J Neuro-onc 12: 1–7, 1992

    Google Scholar 

  31. Constam DB, Philipp J, Malipiero UV, Ten Dijke P, Schachner M, Fontana A: Differential expression of transforming growth factor-beta 1,-beta 2, and-beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol 148(5): 1404–1410, 1992

    Google Scholar 

  32. Fontana A, Kristensen F, Dubs R, Gemsa D, Weber E: Production of prostaglandin E and an interleukin-1 like factor by cultured astrocytes and C6 glioma cells. J Immunol 129(6): 2413–2419, 1982

    Google Scholar 

  33. Sung CC, Pearl DK, Coons SW, Scheithauer BW, Johnson PC, Yates AJ: Gangliosides as diagnostic markers of human astrocytomas and primitive neuroectodermal tumors. Cancer 74(11): 3010–3022, 1994

    Google Scholar 

  34. Grayson G, Ladisch S: Immunosuppression by human gangliosides. II. Carbohydrate structure and inhibition of human NK activity. Cellular Immunology 139(1): 18–29, 1992

    Google Scholar 

  35. Li R, Ladisch S: Abrogation of shedding of immunosuppressive neuroblastoma gangliosides. Cancer Res 56: 4602–4605, 1996

    Google Scholar 

  36. Hahne M, Rimold D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J-C, Tschopp J: Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274: 1363–1366, 1996

    Google Scholar 

  37. Wojtowicz-Praga S, Verma UM, Wakefield L, Esteban JM, Hartmann D, Mazumder A: Modulation of B16 melanoma growth and metastasis by anti-transforming growth factor β antibody and interleukin-2. J Immunother 19(3): 169–175, 1996

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The University of Colorado Health Sciences Center, Denver, CO, USA

    Andrew M Donson & Nicholas K Foreman

  2. The Children's Hospital, Denver, CO, USA

    Nicholas K Foreman

Authors
  1. Andrew M Donson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas K Foreman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Donson, A.M., Foreman, N.K. Adenovirus Mediated Gene Therapy in a Glioblastoma Vaccine Model; Specific Antitumor Immunity and Abrogation of Immunosuppression. J Neurooncol 40, 205–214 (1998). https://doi.org/10.1023/A:1006106026317

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006106026317

Search

Navigation