, Volume 14, Issue 2, pp 333–344 | Cite as

Oncolytic Virotherapy for the Treatment of Malignant Glioma

  • Paul M. Foreman
  • Gregory K. Friedman
  • Kevin A. Cassady
  • James M. Markert


Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with standard-of-care treatments, novel treatment strategies are needed. The concept of virotherapy for the treatment of malignant tumors dates back more than a century and can be divided into replication-competent oncolytic viruses and replication-deficient viral vectors. Oncolytic viruses are designed to selectively target, infect, and replicate in tumor cells, while sparing surrounding normal brain. A host of oncolytic viruses has been evaluated in early phase human trials with promising safety results, but none has progressed to phase III trials. Despite the 25 years that has passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma, much remains to be learned about the use of this therapy, including its mechanism of action, optimal treatment paradigm, appropriate targets, and integration with adjuvant agents. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care.


Glioma Glioblastoma Oncolytic virus Viral therapy Virotherapy 

Supplementary material

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  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.CrossRefPubMedGoogle Scholar
  2. 2.
    Parker JN, Bauer DF, Cody JJ, Markert JM. Oncolytic viral therapy of malignant glioma. Neurotherapeutics 2009;6:558-569.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996.CrossRefPubMedGoogle Scholar
  4. 4.
    Hulou MM, Cho CF, Chiocca EA, Bjerkvig R. Experimental therapies: gene therapies and oncolytic viruses. Handb Clin Neurol 2016;134:183-197.CrossRefPubMedGoogle Scholar
  5. 5.
    Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-760.CrossRefPubMedGoogle Scholar
  6. 6.
    Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396-401.CrossRefPubMedGoogle Scholar
  7. 7.
    Kaufmann JK, Chiocca EA. Glioma virus therapies between bench and bedside. Neuro Oncol 2014;16:334-351.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    DePace N. Sulla scomparsa di un enorme cancro vegetante del callo dell’utero senza cura chirurgica. Ginecologia (France) 1912:82-88.Google Scholar
  9. 9.
    Higgins GK, Pack GT. Virus therapy in the treatment of tumors. Bull Hosp Joint Dis 1951;12:379-382.PubMedGoogle Scholar
  10. 10.
    Pack GT. Note on the experimental use of rabies vaccine for melanomatosis. AMA Arch Derm Syphilol 1950;62:694-695.CrossRefPubMedGoogle Scholar
  11. 11.
    Bluming AZ, Ziegler JL. Regression of Burkitt's lymphoma in association with measles infection. Lancet 1971;2:105-106.CrossRefPubMedGoogle Scholar
  12. 12.
    Taqi AM, Abdurrahman MB, Yakubu AM, Fleming AF. Regression of Hodgkin's disease after measles. Lancet 1981;1:1112.CrossRefPubMedGoogle Scholar
  13. 13.
    Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 2015;33:2780-2788.CrossRefPubMedGoogle Scholar
  14. 14.
    Wheeler LA, Manzanera AG, Bell SD, et al. Phase 2 multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro Oncol 2016;18:1137-1145.CrossRefPubMedGoogle Scholar
  15. 15.
    Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991;252:854-856.CrossRefPubMedGoogle Scholar
  16. 16.
    Markert JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 2000;7:867-874.CrossRefPubMedGoogle Scholar
  17. 17.
    Rampling R, Cruickshank G, Papanastassiou V, et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 2000;7:859-866.CrossRefPubMedGoogle Scholar
  18. 18.
    Wollmann G, Ozduman K, van den Pol AN. Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates. Cancer J 2012;18:69-81.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    He B, Gross M, Roizman B. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A 1997;94:843-848.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Whitley RJ, Kern ER, Chatterjee S, Chou J, Roizman B. Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models. J Clin Invest 1993;91:2837-2843.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Goldstein DJ, Weller SK. Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant. Virology 1988;166:41-51.CrossRefPubMedGoogle Scholar
  22. 22.
    Coen DM, Goldstein DJ, Weller SK. Herpes simplex virus ribonucleotide reductase mutants are hypersensitive to acyclovir. Antimicrob Agents Chemother 1989;33:1395-1399.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1995;1:938-943.CrossRefPubMedGoogle Scholar
  24. 24.
    Hunter WD, Martuza RL, Feigenbaum F, et al. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates. J Virol 1999;73:6319-6326.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Sundaresan P, Hunter WD, Martuza RL, Rabkin SD. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J Virol 2000;74:3832-3841.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Markert JM, Liechty PG, Wang W, et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther 2009;17:199-207.CrossRefPubMedGoogle Scholar
  27. 27.
    Markert JM, Razdan SN, Kuo HC, M et al. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther 2014;22:1048-1055.Google Scholar
  28. 28.
    Advani SJ, Sibley GS, Song PY, et al. Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors. Gene Ther 1998;5:160-165.CrossRefPubMedGoogle Scholar
  29. 29.
    Bradley JD, Kataoka Y, Advani S, et al. Ionizing radiation improves survival in mice bearing intracranial high-grade gliomas injected with genetically modified herpes simplex virus. Clin Cancer Res 1999;5:1517-1522.PubMedGoogle Scholar
  30. 30.
    Friedman GK, Langford CP, Coleman JM, et al. Engineered herpes simplex viruses efficiently infect and kill CD133+ human glioma xenograft cells that express CD111. J Neurooncol 2009;95:199-209.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Friedman GK, Moore BP, Nan L, et al. Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses. Neuro Oncol 2016;18:227-235.CrossRefPubMedGoogle Scholar
  32. 32.
    Papanastassiou V, Rampling R, Fraser M, et al. The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther 2002;9:398-406.CrossRefPubMedGoogle Scholar
  33. 33.
    Harrow S, Papanastassiou V, Harland J, et al. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther 2004;11:1648-1658.CrossRefPubMedGoogle Scholar
  34. 34.
    Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci U S A 2000;97:2208-2213.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ackermann M. The construction, selection, characterization, and application of recombinant herpes viruses. Zentralbl Veterinarmed B 1988;35:379-396.PubMedGoogle Scholar
  36. 36.
    Todo T, Martuza RL, Rabkin SD, Johnson PA. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci U S A 2001;98:6396-6401.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Whyte P, Williamson NM, Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell 1989;56:67-75.CrossRefPubMedGoogle Scholar
  38. 38.
    Fueyo J, Gomez-Manzano C, Alemany R, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000;19:2-12.CrossRefPubMedGoogle Scholar
  39. 39.
    Bischoff JR, Kirn DH, Williams A, t al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274:373-376.Google Scholar
  40. 40.
    O'Shea CC, Johnson L, Bagus B, et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004;6:611-623.CrossRefPubMedGoogle Scholar
  41. 41.
    Chiocca EA, Abbed KM, Tatter S, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther 2004;10:958-966.CrossRefPubMedGoogle Scholar
  42. 42.
    Xia ZJ, Chang JH, Zhang L, et al. [Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus]. Ai Zheng 2004;23:1666-1670.PubMedGoogle Scholar
  43. 43.
    Garber K. China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006;98:298-300.CrossRefPubMedGoogle Scholar
  44. 44.
    Fueyo J, Alemany R, Gomez-Manzano C, et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst 2003;95:652-660.CrossRefPubMedGoogle Scholar
  45. 45.
    Yokoyama T, Iwado E, Kondo Y, et al. Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Ther 2008;15:1233-1239.CrossRefPubMedGoogle Scholar
  46. 46.
    Kane A, Yang I. Interferon-gamma in brain tumor immunotherapy. Neurosurg Clin N Am 2010;21:77-86.CrossRefPubMedGoogle Scholar
  47. 47.
    Strong JE, Coffey MC, Tang D, Sabinin P, Lee PW. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J 1998;17:3351-3362.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 1994;91:7727-7731.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Gong J, Mita MM. Activated ras signaling pathways and reovirus oncolysis: an update on the mechanism of preferential reovirus replication in cancer cells. Front Oncol 2014;4:167.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Yang WQ, Lun X, Palmer CA, et al. Efficacy and safety evaluation of human reovirus type 3 in immunocompetent animals: racine and nonhuman primates. Clin Cancer Res 2004;10:8561-7856.CrossRefPubMedGoogle Scholar
  51. 51.
    Forsyth P, Roldan G, George D, et al. A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol Ther 2008;16:627-632.CrossRefPubMedGoogle Scholar
  52. 52.
    Kicielinski KP, Chiocca EA, Yu JS, Gill GM, Coffey M, Markert JM. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol Ther 2014;22:1056-1062.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Lei N, Shen FB, Chang JH, et al. An oncolytic adenovirus expressing granulocyte macrophage colony-stimulating factor shows improved specificity and efficacy for treating human solid tumors. Cancer Gene Ther 2009;16:33-43.CrossRefPubMedGoogle Scholar
  54. 54.
    Alexander DJ, Allan WH. Newcastle disease virus pathotypes. Avian Pathol 1974;3:269-278.CrossRefPubMedGoogle Scholar
  55. 55.
    Flanagan AD, Love R, Tesar W. Propagation of Newcastle disease virus in Ehrlich ascites cells in vitro and in vivo. Proc Soc Exp Biol Med 1955;90:82-86.CrossRefPubMedGoogle Scholar
  56. 56.
    Lorence RM, Reichard KW, Katubig BB, et al. Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 1994;86:1228-1233.CrossRefPubMedGoogle Scholar
  57. 57.
    Lorence RM, Katubig BB, Reichard KW, et al. Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 1994;54:6017-6021.PubMedGoogle Scholar
  58. 58.
    Csatary LK, Bakacs T. Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 1999;281:1588-1589.CrossRefPubMedGoogle Scholar
  59. 59.
    Csatary LK, Gosztonyi G, Szeberenyi J, et al. MTH-68/H oncolytic viral treatment in human high-grade gliomas. J Neurooncol 2004;67:83-93.CrossRefPubMedGoogle Scholar
  60. 60.
    Wagner S, Csatary CM, Gosztonyi G, et al. Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid. APMIS 2006;114:731-743.CrossRefPubMedGoogle Scholar
  61. 61.
    Freeman AI, Zakay-Rones Z, Gomori JM, et al. Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 2006;13:221-228.CrossRefPubMedGoogle Scholar
  62. 62.
    Yanagi Y. The cellular receptor for measles virus—elusive no more. Rev Med Virol 2001;11:149-156.CrossRefPubMedGoogle Scholar
  63. 63.
    Jurianz K, Ziegler S, Garcia-Schuler H, et al. Complement resistance of tumor cells: basal and induced mechanisms. Mol Immunol 1999;36:929-939.CrossRefPubMedGoogle Scholar
  64. 64.
    Peng KW, Facteau S, Wegman T, O'Kane D, Russell SJ. Non-invasive in vivo monitoring of trackable viruses expressing soluble marker peptides. Nat Med 2002;8:527-531.CrossRefPubMedGoogle Scholar
  65. 65.
    Phuong LK, Allen C, Peng KW, et al. Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res 2003;63:2462-2469.PubMedGoogle Scholar
  66. 66.
    Myers R, Harvey M, Kaufmann TJ, et al. Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas. Hum Gene Ther 2008;19:690-698.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Gromeier M, Alexander L, Wimmer E. Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants. Proc Natl Acad Sci U S A 1996;93:2370-2375.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E. Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci U S A 2000;97:6803-6808.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Merrill MK, Bernhardt G, Sampson JH, Wikstrand CJ, Bigner DD, Gromeier M. Poliovirus receptor CD155-targeted oncolysis of glioma. Neuro Oncol 2004;6:208-217.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Goetz C, Dobrikova E, Shveygert M, Dobrikov M, Gromeier M. Oncolytic poliovirus against malignant glioma. Future Virol 2011;6:1045-1058.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Dobrikova EY, Broadt T, Poiley-Nelson J, et al. Recombinant oncolytic poliovirus eliminates glioma in vivo without genetic adaptation to a pathogenic phenotype. Mol Ther 2008;16:1865-1872.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Pol JG, Marguerie M, Arulanandam R, Bell JC, Lichty BD. Panorama from the oncolytic virotherapy summit. Mol Ther 2013;21:1814-1818.CrossRefPubMedCentralGoogle Scholar
  73. 73.
    Geletneky K, Herrero YCM, Rommelaere J, Schlehofer JR. Oncolytic potential of rodent parvoviruses for cancer therapy in humans: a brief review. J Vet Med B Infect Dis Vet Public Health 2005;52:327-330.CrossRefPubMedGoogle Scholar
  74. 74.
    Rommelaere J, Geletneky K, Angelova AL, et al. Oncolytic parvoviruses as cancer therapeutics. Cytokine Growth Factor Rev 2010;21:185-195.CrossRefPubMedGoogle Scholar
  75. 75.
    Rommelaere J, Cornelis JJ. Antineoplastic activity of parvoviruses. J Virol Methods 1991;33:233-251.CrossRefPubMedGoogle Scholar
  76. 76.
    Herrero YCM, Cornelis JJ, Herold-Mende C, Rommelaere J, Schlehofer JR, Geletneky K. Parvovirus H-1 infection of human glioma cells leads to complete viral replication and efficient cell killing. Int J Cancer 2004;109:76-84.CrossRefGoogle Scholar
  77. 77.
    Geletneky K, Kiprianova I, Ayache A, et al. Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models. Neuro Oncol 2010;12:804-814.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Geletneky K, Huesing J, Rommelaere J, et al. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol. BMC Cancer 2012;12:99.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Harrington KJ, Puzanov I, Hecht JR, et al. Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy. Expert Rev Anticancer Ther 2015;15:1389-1403.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  • Paul M. Foreman
    • 1
  • Gregory K. Friedman
    • 2
  • Kevin A. Cassady
    • 3
  • James M. Markert
    • 1
    • 2
  1. 1.Department of NeurosurgeryUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of PediatricsUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Nationwide Children’s HospitalColumbusUSA

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