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Background. Herpes simplex virus (HSV) 1716 is a selectively replicating oncolytic virus. Our objective was to assess the potential efficacy of HSV1716 in patients with oral squamous cell carcinoma (SCC) by intratumoral injection. Methods. Twenty patients with oral SCC had a single intratumoral injection of HSV1716 at a dose of 105 pfu (plaque forming unit) or 5 × 105 pfu. Injections were done at 1, 3, or 14 days before surgical resection. The tumors were assessed for evidence of viral replication and necrosis. Immunologic response to virus and toxicity was also assessed. Results. Intratumoral injections were well tolerated with no adverse effects. Evidence of biological activity was lacking, with no increase in detectable virus in tumor samples. Conclusion. Intratumoral injection of HSV1716 is safe but with little evidence for viral replication or efficacy. Further studies at higher doses are required to determine the potential efficacy of this virus in head and neck cancer. © 2008 Wiley Periodicals, Inc. Head Neck 2008 [ABSTRACT FROM AUTHOR]

Chinese hamster ovary (CHO) cells are traditionally regarded as nonpermissive cells for herpes simplex virus type 1 (HSV-1) infection as they lack the specific entry receptors, and modified CHO cells have been instrumental in the identification of HSV-1 receptors in numerous studies. In this report we demonstrate that the HSV-1 strain 17+ variant HSV1716 is able to infect unmodified CHO cells but only if the virus is propagated in baby hamster kidney (BHK) cells. Infection of CHO cells by BHK-propagated HSV1716 results in expression of immediate-early, early, and late viral genes, and infectious progeny virions are produced. In normally cultured CHO cells, up to a maximum of 50% of cells were permissive for BHK-propagated HSV1716 infection, with 24 h of serum starvation increasing this to 100% of CHO cells, suggesting that the mechanism used by BHK-propagated virus to infect CHO cells was cell cycle dependent. The altered tropism of HSV1716 was also evident in another nonpermissive mouse melanoma cell line and is an exclusive property resulting from propagation of the virus using BHK cells, as viruses propagated on Vero, C8161 (a human melanoma cell line), or indeed, CHO cells were completely unable to infect either CHO or mouse melanoma cells. [ABSTRACT FROM AUTHOR]

Background: HSV1790 is an oncolytic virus generated by inserting the enzyme nitroreductase (NTR) into the virus HSV1716. NTR converts the prodrug CB1954 into an active alkylating agent., Materials and Methods: In vitro, 3T6 cells (non permissive to HSV) were used in order to distinguish between virus-induced cytopathic effect and cell death due to activated prodrug. In vivo, xenograft models were injected with HSV1790 (10(5)-10(9) PFU) with or without CB1954 (max 80mg/kg) and tumor volume recorded regularly. Biodistribution of HSV1790 was determined immunohistochemically and by PCR., Results: HSV1790 + CB1954 in vitro was more effective at killing tumor cells than the virus or the prodrug alone. In vivo, the combination reduced tumor volume and increased survival compared to treatment with HSV1790 or CB1954 alone. Following systemic administration of HSV1790, viral replication was detected in tumors, but not organs., Conclusion: HSV1790 + prodrug enhances tumor cell killing in vitro and reduces tumor volume and increases survival in vivo.

Background: The neurotropic herpes simplex virus mutant HSV1716 lacks the gene encoding the virulence factor ICP34.5 and cannot replicate in non-dividing cells where proliferating cell nuclear antigen (PCNA) is not actively engaged in cellular DNA synthesis. In the brain, tumoral expression of PCNA therefore confers on it oncolytic specificity and may determine its efficacy. Three phase I trials in glioma patients and one in metastatic melanoma patients have established that HSV1716 is safe and replicates selectively in tumour tissue. Here we examine the in situ PCNA profiles of common human metastatic brain tumours and determine their in vitro permissivity for HSV1716 replication to ascertain their suitability for HSV1716 therapy., Methods: Histological sections of tumour biopsies obtained from patients undergoing craniotomies were stained for PCNA expression. The replicative ability of HSV wild-type (17(+)) and mutant (1716) viruses was assessed in tissue cultures of the same tumour biopsies and in cancer cell lines by plaque assay., Results: Biopsies of all 10 metastatic tumours (3 melanoma, 4 carcinoma and 3 adenocarcinoma) as well as 4 glioblastoma multiforme were positive for PCNA immunoexpression and supported the replication of HSV1716. The PCNA-positive cells in the metastatic tumours were distributed comparatively in larger and more contiguous areas than in glioblastoma (1.69 +/- 1.61 mm(2) vs. 0.73 +/- 0.77 mm(2)) and numbered 29.0 +/- 12.4 and 12.6 +/- 4.7%, respectively., Conclusions: The results show that human cerebral metastatic tumours have generally larger and more contiguous proliferative areas, support efficient HSV1716 replication, and are thus potential candidates for such oncolytic viral therapy., (Copyright 2003 John Wiley & Sons, Ltd.)