Abstract
BackgroundThe NV1020 oncolytic herpes simplex virus type-1 has shown significant promise for the treatment of many different types of tumors in experimental animal models and human trials. Previously, we described the construction and use of the NV1020-like virus OncSyn to treat human breast tumors implanted in nude mice. The syncytial mutation gKsyn1 (Ala-to-Val at position 40) was introduced into the OncSyn viral genome cloned into a bacterial artificial chromosome using double-red mutagenesis in E. coli to produce the OncdSyn virus carrying syncytial mutations in both gB(syn3) and gK(syn1).ResultsThe OncdSyn virus caused extensive virus-induced cell fusion in cell culture. The oncolytic potential of the OncSyn and OncdSyn viruses was tested in the highly metastatic syngeneic mouse model system, which utilizes 4T1 murine mammary cancer cells implanted within the interscapular region of Balb/c mice. Mice were given three consecutive intratumor injections of OncSyn, OncdSyn, or phosphate buffered saline four days apart. Both OncSyn and OncdSyn virus injections resulted in significant reduction of tumor sizes (p < 0.05) compared to control tumors. Virus treated mice but not controls showed a marked reduction of metastatic foci in lungs and internal organs. Mouse weights were not significantly impacted by any treatment during the course of the entire study (p = 0.296).ConclusionThese results show that the attenuated, but highly fusogenic OncSyn and OncdSyn viruses can effectively reduce primary and metastatic breast tumors in immuncompetent mice. The available bac-cloned OncSyn and OncdSyn viral genomes can be rapidly modified to express a number of different anti-tumor and immunomodulatory genes that can further enhance their anti-tumor potency.
Highlights
The NV1020 oncolytic herpes simplex virus type-1 has shown significant promise for the treatment of many different types of tumors in experimental animal models and human trials
As we reported previously for the OncSyn virus, the bac-cloned OncdSyn viral genome was subjected to PCR-diagnostic analysis and direct sequencing of specific genomic loci to confirm the presence of the syn3 and syn1 mutations and the previously engineered deletion/insertion at the γ1 34.5 locus
Phenotypic characteristics of the OncSyn and OncdSyn viruses on Vero and 4T1 cells The plaque morphology of the HSV-1(F), OncSyn and OncdSyn viruses was examined on Vero cells and 4T1 cancer cells (Balb/c spontaneous mammary adenocarcinomaderived) [40] as described in Materials and Methods (Fig. 2)
Summary
The NV1020 oncolytic herpes simplex virus type-1 has shown significant promise for the treatment of many different types of tumors in experimental animal models and human trials. The syncytial mutation gKsyn (Ala-to-Val at position 40) was introduced into the OncSyn viral genome cloned into a bacterial artificial chromosome using double-red mutagenesis in E. coli to produce the OncdSyn virus carrying syncytial mutations in both gB(syn3) and gK(syn). The recent availability of cloned HSV genomes into bacterial artificial chromosome vectors greatly facilitates the rapid construction of new recombinant viruses carrying multiple transgenes of interest [8,9,10]. Tumor treatment with oncolytic HSV has been shown to induce anti-tumor immune responses [11,12,13,14,15]. The majority of people are seropositive for HSV1, oncolytic virotherapy with HSV is not limited by preexisting anti-HSV immunity [16,17], and in at least one example, preexisting immunity to HSV-1 enhanced antitumor immune responses [18]
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