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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

Abstract

We have previously demonstrated the safety of intratumoural administration of the selectively replication-competent herpes simplex virus mutant HSV1716 in patients with high-grade glioma (HGG). Here we show its potential for efficacy by demonstrating that the virus survives and replicates when injected into the tumours of patients. Since HSV replication is a cytolytic process it must result in tumour cell killing. Twelve patients with biopsy-verified HGG received an intratumoural injection of 105 plaque-forming units (p.f.u.) of HSV1716. Four to 9 days after inoculation, tumours were removed and assayed for evidence of viral replication. In two patients, HSV1716, in excess of the input dose was recovered from the injection site. HSV DNA was detected by PCR at the sites of inoculation in 10 patients and at distal tumour sites in four. HSV-specific antigen was detected in tumour tissue from two patients. In five patients an immunological response to HSV1716, as detected by changes in levels of IgG and IgM, was demonstrated. This study demonstrates that HSV1716 replicates in HGG without causing toxicity in both HSV-seropositive and -seronegative patients.

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References

  1. Dolan A., McKie E., MacLean A.R., McGeoch D.J. . Status of the ICP34.5 gene in herpes simplex virus type 1 strain 17 J Gen Virol 1992 73: 971 971

    Article  CAS  PubMed  Google Scholar 

  2. MacLean A.R. et al. Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17+ between immediate early gene 1 and the ‘a’ sequence J Gen Virol 1991 72: 631 631

    Article  CAS  PubMed  Google Scholar 

  3. Brown S.M. et al. Cell type and cell state determine differential in vitro growth of non-neurovirulent ICP34.5-negative herpes simplex virus types 1 and 2 J Gen Virol 1994 75: 2367 2367

    Article  CAS  PubMed  Google Scholar 

  4. McKie E.A. et al. Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours – evaluation of a potentially effective clinical therapy Br J Cancer 1996 74: 745 745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kesari S. et al. Therapy of experimental human brain tumors using a neuroattenuated herpes simplex virus mutant Lab Invest 1995 73: 636 636

    CAS  PubMed  Google Scholar 

  6. Randazzo B.P. et al. Treatment of experimental intracranial murine melanoma with a neuroattenuated herpes simplex virus 1 mutant Virology 1995 211: 94 94

    Article  CAS  PubMed  Google Scholar 

  7. Lasner T.M. et al. Therapy of a murine model of pediatric brain tumors using a herpes simplex virus type-1 ICP34.5 mutant and demonstration of viral replication within the CNS J Neuropathol Exp Neurol 1996 55: 1259 1259

    Article  CAS  PubMed  Google Scholar 

  8. McKie E.A., Brown S.M., MacLean A.R., Graham D.I. . Histopathological responses in the CNS following inoculation with a non-neurovirulent mutant (1716) of herpes simplex virus type 1 (HSV 1): relevance for gene and cancer therapy Neuropathol Appl Neurobiol 1998 24: 367 367

    Article  CAS  PubMed  Google Scholar 

  9. Rampling R. et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma Gene Therapy 2000 7: 859 859

    Article  CAS  PubMed  Google Scholar 

  10. MacKie R.M., Stewart B., Brown S.M. . Intralesional injection of herpes simplex virus 1716 in metastatic melanoma Lancet 2001 357: 525 525

    Article  CAS  PubMed  Google Scholar 

  11. Markert J.M. et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial Gene Therapy 2000 7: 867 867

    Article  CAS  PubMed  Google Scholar 

  12. Zweerink H.J., Stanton L.W. . Immune response to herpes simplex virus infections: virus-specific antibodies in sera from patients with recurrent facial infections Infect Immun 1981 31: 624 624

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Brown S.M., Ritchie D.A., Subak-Sharpe J.H. . Genetic studies with herpes simplex virus type 1. The isolation of temperature-sensitive mutants, their arrangement into complementation groups and recombination analysis leading to a linkage map J Gen Virol 1973 18: 329 329

    Article  CAS  PubMed  Google Scholar 

  14. Kennedy P.G. et al. A cultured human oligodendroglioma cell line and herpes simplex virus-infected cells share antigenic determinants J Neurooncol 1987 4: 389 389

    Article  CAS  PubMed  Google Scholar 

  15. Puchhammer-Stockl E. et al. Establishment of PCR for the early diagnosis of herpes simplex encephalitis J Med Virol 1990 32: 77 77

    Article  CAS  PubMed  Google Scholar 

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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 9, 398–406 (2002). https://doi.org/10.1038/sj.gt.3301664

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