Journal of Neuro-Oncology

, Volume 123, Issue 3, pp 465–471 | Cite as

Cytomegalovirus and glioblastoma; controversies and opportunities

  • Sean E. Lawler
Editors' Invited Manuscript


One of the more polarized ongoing debates in the brain tumor field over recent years has centered on the association of cytomegalovirus (CMV) with glioblastoma. Several laboratories have reported the presence of CMV antigens in glioblastoma patient specimens, whereas others have failed to detect them. CMV genomic DNA and mRNAs have been detected by PCR, but not in next-generation sequencing studies. CMV promotes high grade glioma progression in a mouse genetic model, and many CMV proteins promote cancer hallmarks in vitro, but actively replicating virus has not been isolated from tumor samples. A consensus is gradually emerging in which the presence of CMV antigens in glioblastoma is increasingly accepted. However, it remains challenging to understand this mechanistically due to the low levels of CMV nucleic acids and the absence of viral replication observed in tumors thus far. Nonetheless, these observations have inspired the development of novel therapeutic approaches based on anti-viral drugs and immunotherapy. The potential benefit of valganciclovir in glioblastoma has generated great interest, but efficacy remains to be established in a randomized trial. Also, early stage immunotherapy trials targeting CMV have shown promise. In the near future we will know more answers to these questions, and although areas of controversy may remain, and the mechanisms and roles of CMV in tumor growth are yet to be clearly defined, this widespread virus may have created important new therapeutic concepts and opportunities for the treatment of glioblastoma.


Cytomegalovirus Glioblastoma Immunotherapy 


  1. 1.
    zur Hausen H (2009) Papillomaviruses in the causation of human cancers—a brief historical account. Virology 384(2):260–265PubMedCrossRefGoogle Scholar
  2. 2.
    Martin D, Gutkind JS (2008) Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene 27(Suppl 2):S31–S42PubMedCrossRefGoogle Scholar
  3. 3.
    Cobbs et al (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62(12):3347–3350PubMedGoogle Scholar
  4. 4.
    Mitchell DA et al (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10(1):10–18PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Scheurer ME et al (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116(1):79–86PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Rahbar A et al (2013) Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol 57(1):36–42PubMedCrossRefGoogle Scholar
  7. 7.
    Libard S et al (2014) Human cytomegalovirus tegument protein pp65 is detected in all intra-and extra-axial brain tumors independent of the tumour type or grade. PLoS ONE 9(9):e108861PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Bhattacharjee B, Renzette N, Kowalik TE (2012) Genetic analysis of cytomegalovirus in malignant gliomas. J Virol 86(12):6815–6824PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Ranganathan P et al (2012) Significant association of multiple human cytomegalovirus genomic loci with glioblastoma multiforme samples. J Virol 86(2):854–864PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Price RL et al (2013) Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res 73(11):3441–3450PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Cobbs CS (2013) Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol 25(6):682–688PubMedCrossRefGoogle Scholar
  12. 12.
    Ludwig A, Hengel H (2009) Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe. Euro Surveill 14(9):26–32PubMedGoogle Scholar
  13. 13.
    Mustakangas P et al (2000) Human cytomegalovirus seroprevalence in three socioeconomically different urban areas during the first trimester: a population-based cohort study. Int J Epidemiol 29(3):587–591PubMedCrossRefGoogle Scholar
  14. 14.
    Staras SAS et al (2006) Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis 43(9):1143–1151PubMedCrossRefGoogle Scholar
  15. 15.
    Murphy E, Shenk T (2008) Human cytomegalovirus genome. Curr Top Immunol 325:1–19Google Scholar
  16. 16.
    Dölken L, Pfeffer S, Koszinowski UH (2009) Cytomegalovirus microRNAs. Virus Genes 38(3):355–364PubMedCrossRefGoogle Scholar
  17. 17.
    Plachter B, Sinzger C, Jahn G (1996) Cell types involved in replication and distribution of human cytomegalovirus. Adv Virus Res 46:195–261PubMedCrossRefGoogle Scholar
  18. 18.
    Taylor-Wiedeman J et al (1991) Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 72(9):2059–2064PubMedCrossRefGoogle Scholar
  19. 19.
    Luo MH et al (2010) Human cytomegalovirus infection causes premature and abnormal differentiation of human neural progenitor cells. J Virol 84(7):3528–3541PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Cobbs CS et al (2007) Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma invasiveness. J Neurooncol 85(3):271–280PubMedCrossRefGoogle Scholar
  21. 21.
    Straat K et al (2009) Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst 101(7):488–497PubMedCrossRefGoogle Scholar
  22. 22.
    Soroceanu L, Akhavan A, Cobbs CS (2008) Platelet-derived growth factor-a receptor activation is required for human cytomegalovirus infection. Nature 455(18):391–396PubMedCrossRefGoogle Scholar
  23. 23.
    Slinger E et al (2010) HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal 3(133):ra58PubMedGoogle Scholar
  24. 24.
    Dziurzynski K et al (2011) Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res 17(14):4642–4649PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Price RL et al (2012) Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/− mice. Cancer Res 72(22):5669–5674PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Taher C et al (2013) High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. PLoS ONE 8(2):e56795PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Baryawno N et al (2011) Detection of human cytomegalovirus in medulloblastoma reveals a potential therapeutic target. J Clin Invest 121(10):4043–4055PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Lau et al (2005) Lack of association of cytomegalovirus with human brain tumors. Mod Pathol 18(6):838–843PubMedCrossRefGoogle Scholar
  29. 29.
    Poltermann S et al (2006) Lack of association of herpesviruses with brain tumors. J Neuro Virol 12(2):90–99Google Scholar
  30. 30.
    Baumgarten P et al (2014) Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro Oncol 16(11):1469–1477PubMedCrossRefGoogle Scholar
  31. 31.
    Hellstrand K, Martner A, Bergstrom T (2013) Valganciclovir in patients with glioblastoma. New Engl J Med 369(21):2066PubMedCrossRefGoogle Scholar
  32. 32.
    Tang KW et al (2013) The landscape of viral expression and host gene fusion and adaptation in human cancer. Nat Commun 4:2513PubMedCentralPubMedGoogle Scholar
  33. 33.
    Renzette N et al (2011) Extensive genome-wide variability of human cytomegalovirus in congenitally infected infants. PLoS Pathog 7:e1001344PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Dziurzynski K et al (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 14(3):246–255PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Huse JT, Aldape K (2014) CMV and glioma—are we there yet? Neuro Oncol 16(11):1433–1434PubMedCrossRefGoogle Scholar
  36. 36.
    Cobbs C (2014) Response to “Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics”. Neuro Oncol 14(3):1435–1436CrossRefGoogle Scholar
  37. 37.
    Stragliotto G et al (2013) Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus positive glioblastoma: a randomized, double-bind, hypothesis generating study. Int J Cancer 133(5):1204–1213PubMedCrossRefGoogle Scholar
  38. 38.
    Soderberg-Naucler C, Rahbar A, Stragliotto G (2013) Survival in patients with glioblastoma treated with valganciclovir. New Engl J Med 369(10):985–986PubMedCrossRefGoogle Scholar
  39. 39.
    Wrensch M et al (2001) Prevalence of antibodies to four herpesviruses among adults with glioma and controls. Am J Epidemiol 154(2):161–165PubMedCrossRefGoogle Scholar
  40. 40.
    Soderberg-Naucler C, Peredo I, Stragliotto G (2013) Valganciclovir in patients with glioblastoma. New Engl J Med 369(21):2066–2067PubMedCrossRefGoogle Scholar
  41. 41.
    Liu C-J, Hu Y-W (2014) Immortal time bias in retrospective analysis: is there a survival benefit in patients with glioblastoma who received prolonged treatment of adjuvant valganciclovir? Int J Cancer 135(1):250–251PubMedCrossRefGoogle Scholar
  42. 42.
    Soderberg-Naucler C et al (2014) Use of Cox regression with treatment status as a time-dependent covariate to re-analyze survival benefit excludes immortal time bias effect in patients with glioblastoma who received prolonged adjuvant treatment with valganciclovir. Int J Cancer 135(1):248–249PubMedCrossRefGoogle Scholar
  43. 43.
    Wick W, Wick A, Platten M (2014) Good maths is needed to understand CMV data in glioblastoma. Int J Cancer 134(12):2991–2992PubMedCrossRefGoogle Scholar
  44. 44.
    Weller M, Soffietti R, Brada M (2014) The legend of cytomegalovirus and glioblastoma lives on. Neuro Oncol 16(1):166PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Wick W, Platten M (2014) CMV infection and glioma, a highly controversial concept struggling in the clinical arena. Neuro Oncol 16(3):332–333PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Cobbs CS (2014) Does valganciclovir have a role in glioblastoma therapy? Neuro Oncol 16(3):330–331PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Hadaczek P et al (2013) Cidofovir: a novel antitumor agent for glioblastoma. Clin Cancer Res 19(23):6473–6483PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Schuessler A, Walker DG, Khanna R (2014) Cytomegalovirus as a novel target for immunotherapy of glioblastoma multiforme. Front Oncol 4:275PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Nair SK, Sampson JH, Mitchell DA (2014) Immunological targeting of cytomegalovirus for glioblastoma therapy. Oncoimmunology 3:e29289PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Nair SK et al (2014) Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin Cancer Res 20(X):2684–2694PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Prins RM, Cloughesy TF, Liau LM (2008) Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 359(5):539–541PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Crough T et al (2012) Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme. Immunol Cell Biol 90(9):872–880PubMedCrossRefGoogle Scholar
  53. 53.
    Ghazi et al (2012) Generation of polyclonal CMV-specific T cells for the adoptive immunotherapy of glioblastoma. J Immunother 35(2):159–168PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Schuessler A et al (2014) Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res 74(13):3466–3476PubMedCrossRefGoogle Scholar
  55. 55.
    Wadman M (2013) NIH mulls rules for validating key results. Nature 500(7560):14–16PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Harvey Cushing Neuro-Oncology Laboratories, Department of NeurosurgeryBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations