Skip to main content
Log in

Preliminary Results of Active Specific Immunization with Modified Tumor Cell Vaccine in Glioblastoma Multiforme

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

Abstract

Object Treatment for glioblastoma multiforme has failed to show any progress for decades. While specific immunization with tumor cells modified with Newcastle-Disease-Virus (NDV) has been reported successful in some extracerebral tumors, its effect on glioblastoma is unknown. We report on 11 patients, in whom this approach was analyzed.

Methods A vaccine was produced from autologous tumor cell cultures of 11 patients with glioblastoma. After completed surgery and radiotherapy an intracutaneous vaccination was performed 4 times with a 2 week interval and finally after 3 months. Local reactions, general side effects and survival were monitored closely.

Results The local reaction of the skin after injection of vaccine increased from 1.67 to 4.05 cm2 in 8 weeks. The skin reaction after parallel injection of inactivated, untreated tumor cells increased from 0.11 to 1.09 cm2. The median survival was 46 weeks (mean 60 weeks). No side effects were noted.

Conclusion Active specific immunization with NDV-modified glioblastoma cells produced a noticeable peripheral immune response. In this preliminary series survival of patients was not significantly longer after active specific immunization than after combined treatment of surgery, radiotherapy and chemotherapy. As there were no side effects, however, active specific immunization may be nobreak considered an alternative in the management of glioblastoma.

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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fine HA, Dear KBG, Loeffler JS, Black PM, Canellos GP: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71: 2585–2597, 1993

    Google Scholar 

  2. Kornblith PL, Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68: 1–17, 1988

    Google Scholar 

  3. Badie B, Black KL: Immunotherapy of primary malignant brain tumors. Crit Rev Neurosurg 4: 89–94, 1994

    Google Scholar 

  4. Holladay FP, Heitz T, Chen YL, Chiga M, Wood GW: Successful treatment of a malignant rat glioma with cytotoxic T lymphocytes. Neurosurgery 31: 528–533, 1992

    Google Scholar 

  5. Jacobs ST, Wilson DJ, Kornblith PL, Grimm EA: In vitro killing of human glioblastoma by interleukin-2-activated autologous lymphocytes. J Neurosurg 64: 114–117, 1986

    Google Scholar 

  6. Lillehei KO, Mitchell DH, Johnson SD, McCleary EL, Kruse CA: Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 28: 16–23, 1991

    Google Scholar 

  7. Oldfield EH, Ram Z, Culver KW, Blaese RM, De Vromm HL, Anderson WF: Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum Gene Ther 4: 39–69, 1993

    Google Scholar 

  8. Mahaley MS Jr, Bigner DD, Dudka LF, Wilds PR, Williams DH, Bouldin TW, Whitaker JN, Bynum JM: Immunobiology of primary intracranial tumors. Part 7: Active immunization of patients with anaplastic human glioma cells: a pilot study. J Neurosurg 59: 201–207, 1983

    Google Scholar 

  9. Bloom HJG, Peckham MJ, Richardson AE, Alexander PA, Payne PM: Glioblastoma multiforme: a controlled trial to assess the value of specific active immunotherapy in patients treated by radical surgery and radiotherapy. Br J Cancer 27: 253–267, 1973

    Google Scholar 

  10. Sawamura Y, de Tribolet N: Immunobiology of brain tumors. In: Symon L, Calliauw L, Cohadon F, Guidetti B, Loew F, Nornes H, Pásztor E. Pertuiset B Pickard JD, Yasargil MG (eds) Advances and Technical Standards in Neurosurgery. Springer-Verlag, Wien, New York, 1990, Volume 17 pp 3–64

    Google Scholar 

  11. Brooks W, Netsky MG, Normansell DE, Horwitz DA: Depressed cell mediated immunity in patients with primary intracranial tumors. J Exp Med 136: 1631–1647, 1972

    Google Scholar 

  12. Brooks WH, Markesbery WR, Gupta GD, Roszman TL: Relationship of lymphocyte invasion and survival of brain tumor patients. Ann Neurol 4: 219–224, 1978

    Google Scholar 

  13. Mahaley MS Jr, Brooks WH, Roszman TL, Bigner DD, Dudka L, Richardson S: Immunobiology of primary intracranial tumors. Part 1: Studies of the cellular and humoral general immune competence of brain-tumor patients. J Neurosurg 46: 467–476, 1977

    Google Scholar 

  14. Miescher S, Whiteside TL, de Tribolet N, von Fliedner V: In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers. J Neurosurg 68: 438–448, 1988

    Google Scholar 

  15. Paine JT, Handa H, Yamasaki T, Yamashita J, Miyatake S: Immunohistochemical analysis of infiltrating lymphocytes in central nervous system tumors. Neurosurgery 18: 766–772, 1986

    Google Scholar 

  16. von Hanwehr RI, Hofman FM, Taylor CR, Apuzzo MLJ: Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies. J Neurosurg 60: 1138–1147, 1984

    Google Scholar 

  17. Tada M, de Tribolet N: Recent advances in immunobiology of brain tumors. J Neuro-Oncol 17: 261–271, 1993

    Google Scholar 

  18. Holladay FP, Choudhuri R, Heitz T, Wood GW: Generation of cytotoxic immune responses during the progression of a rat glioma. J Neurosurg 80: 90–96, 1994

    Google Scholar 

  19. Klein B, Loven D, Lurie H, Rakowsky E, Nyska A, Levin I, Klein T: The effect of irradiation on expression of HLA class I antigens in human brain tumors in culture. J Neurosurg 80: 1074–1077, 1994

    Google Scholar 

  20. Momozaki N, Oh-Uchida M, Tabuchi K, Ikezaki K, Hori K: Suppression of anchorage-independent growth of human glioblastoma cell by major histocompatibility complex class I gene-transfection. J Neurosurg 76: 845–849, 1992

    Google Scholar 

  21. Nitta T, Ebato M, Sato K: Association of malignant glioma with the human leukocyte antigen, HLA-A24(9). Neurosurg Rev 17: 211–215, 1994

    Google Scholar 

  22. Marchand M, Brasseur F, van der Bruggen P, Coulie P, Boon T: Perspectives for immunization of HLA-A1 patients carrying a malignant melanoma expressing gene MAGE-1. Dermatology 186: 278–280, 1993

    Google Scholar 

  23. Rimoldi D, Romero P, Carrel S: The human melanoma antigen-encoding gene, MAGE-1, is expressed by other tumour cells of neuroectodermal origin such as glioblastomas and neuroblastomas. Int J Cancer 54: 527–528, 1993

    Google Scholar 

  24. Traversi C, van der Bruggen P, Luescher IF, Lurquin C, Chomez P, van Pel A, de Plaen E, Amar-Costesec A, Boon T: A nonapeptide encoded by human geneMAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J Exp Med 176: 1453–1457, 1992

    Google Scholar 

  25. Gately MK, Glaser M, McCarron RM, Dick SJ, Dick MD, Mettetal RW Jr, Kornblith PL: Mechanisms by which human gliomas may escape cellular immune attack. Acta Neurochirurgica 64: 175–197, 1982

    Google Scholar 

  26. von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle Disease Virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18: 1159–1166, 1988

    Google Scholar 

  27. Maxwell M, Galanopoulos T, Neville-Golden J, Antoniades HN: Effect of the expression of transforming growth factor-β2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76: 799–804, 1992

    Google Scholar 

  28. Naujoks G, Schmitz A, Schramm J, Wiestler OD, Schirrmacher V: Peripheral immunization against malignant rat glioma can induce effective anti-tumor immunity in the brain. Int J Oncol 6: 759–765, 1995

    Google Scholar 

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

    Google Scholar 

  30. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Expl Metastasis 5: 147–156, 1987

    Google Scholar 

  31. Schirrmacher V: Active specific immunotherapy - a new modality of cancer treatment involving the patient's own immune system. Onkologie 16: 290–296, 1993

    Google Scholar 

  32. Cassel WA, Garret RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863–868, 1965

    Google Scholar 

  33. Lorence RM, Rood PA, Kelley KW: Newcastle Disease Virus as an antineoplastic agent: induction of tumor necrosis factor-β and augmentation of its cytotoxicity. J Natl Cancer Inst 80: 1305–1312, 1988

    Google Scholar 

  34. Marcus PI, Svitlik C, Sekellick MJ: Interferon induction by viruses. X. A model for interferon induction by Newcastle Disease Virus. J Gen Virol 64: 2419–2431, 1983

    Google Scholar 

  35. Schirrmacher V: Postoperative activation of tumor-specific T-cells as a means to achieve immune control of minimal residual disease. In: Fortner JG, Rhoads JE (eds) Accomplishments in Cancer Research, J.P. Lippincott Company, Philadelphia, 1986, pp 218–231

    Google Scholar 

  36. Schirrmacher V, Ahlert T, Heicappell R, Appelhans B, von Hoegen P: Successful application of non oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19–49, 1986

    Google Scholar 

  37. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle Disease Virus. III. Potentiation of tumor-specific cytolytic T Cell activity via induction of Interferon-β/β. Cell Immunol 126: 80–90, 1990

    Google Scholar 

  38. Bohle W, Schlag P, Liebrich W, Hohenberger P, Manasterski M, Möller P, Schirrmacher V: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent newcastle disease virus. Cancer 66: 1517–1523, 1990

    Google Scholar 

  39. Cassel WA, Murray DR, Phillips HS: Aphase II study on the postsurgical management of stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer 52: 856–860, 1983

    Google Scholar 

  40. Hoover HC, Surdike MG, Dangel RB, Peters LC, Hanna MG: Prospectively randomized trial of adjuvant active-specific immunotherapy for human colorectal cancer. Cancer 55: 1236–1243, 1985

    Google Scholar 

  41. Hoover HC Jr, Brandhorst JS, Peters LC, Surdyke MG, Takeshita Y, Madariaga J, Muenz LR, Hanna MG Jr: Adjuvant active specific immunotherapy for human colorectal cancer: 6,5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 11: 390–399, 1993

    Google Scholar 

  42. Schlag P, Manasterski M, Gerneth T, Hohenberger P, Dueck M, Herfarth C, Liebrich W, Schirrmacher V: Active specific immunotherapy with Newcastle-diseasevirus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunoth 35: 325–330, 1992

    Google Scholar 

  43. Tallberg T, Kalima T, Haltunen P, Tykkä H, Mahlberg K, Matous B, Sundell B: Postoperative active specific immunotherapy with supportive measures in patients suffering from recurrent metastazised melanoma: Case report of six patients. J Surg Oncol 33: 115–119, 1986

    Google Scholar 

  44. Kniker WT, Anderson CT, Roumiantzeff M: The multi-test system: a standardized approach to evaluation of delayed hypersensitivity and cell-mediated immunity. Ann Allergy 43: 73–79, 1979

    Google Scholar 

  45. Borenfreund E, Puerner JA: Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol Lett 24: 119–124, 1985

    Google Scholar 

  46. Mahaley MS Jr, Gillespie GY, Gillespie RP, Watkins PJ, Bigner DD, Wikstrand CJ, MacQueen JM, Sanfilippo F: Immunobiology of primary intracranial tumors. Part 8: Serological responses to active immunization of patients with anaplastic gliomas. J Neurosurg 59: 208–216, 1983

    Google Scholar 

  47. Irie RK, Irie K, Morton DL: Natural antibody in human serum to a neoantigen in human cultured cells grown in fetal bovine serum. JNCI 52: 1051–1058, 1974

    Google Scholar 

  48. Hamburger RN, Pious DA, Mills SE: Antigenic specificities acquired from the growth medium by cells in tissue culture. Immunology 6: 439–449, 1963

    Google Scholar 

  49. Zülch KJ: Brain tumors. Their biology and pathology. Springer-Verlag, Berlin, Heidelberg, New York, Tokyo, 1986

    Google Scholar 

  50. Kuppner MC, Hamou MF, Sawamura Y, Bodmer S, de Tribolet N: Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor β2. J Neurosurg 71: 211–217, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schneider, T., Gerhards, R., Kirches, E. et al. Preliminary Results of Active Specific Immunization with Modified Tumor Cell Vaccine in Glioblastoma Multiforme. J Neurooncol 53, 39–46 (2001). https://doi.org/10.1023/A:1011856406683

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1011856406683

Navigation