Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures.

Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Gene therapy (Impact Factor: 4.75). 09/2009; 16(12):1477-82. DOI: 10.1038/gt.2009.94
Source: PubMed

ABSTRACT Oncolytic herpes simplex viruses type 1 (oHSVs) such as G47Delta and G207 are genetically engineered for selective replication competence in cancer cells. Several factors can influence the overall effectiveness of oHSV tropism, including HSV-1 receptor expression, extracellular matrix milieu and cellular permissiveness. We have taken advantage of human prostate organ cultures derived from radical prostatectomies to investigate oHSV tropism. In this study, we show that both G47Delta and G207 specifically replicate in epithelial cells of the prostatic glands but not in the surrounding stroma. In contrast, both the epithelial and stromal cell compartments were readily infected by wild-type HSV-1. Analysis of oHSV replication in prostate surgical specimens 3 days post infection showed that G47Delta generated approximately 30-fold more viral progeny than did G207. This correlated with the enhanced expression of G47Delta-derived glycoprotein gB protein levels as compared with G207. In benign prostate tissues, G207 and G47Delta titers were notably reduced, whereas strain F titers were maintained at similar levels compared with prostate cancer specimens. Overall, our results show that these oncolytic herpes vectors show both target specificity and replication competence in human prostate cancer specimens and point to the utility of using human prostate organ cultures in assessing oHSV tropism and cellular specificity.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Viruses have long been considered potential anticancer treatments. Wild-type viruses have been tested as anticancer agents in clinical trials since the 1960s. The possibility of viral oncolysis as an alternate cancer therapy was transformed by the emergence of modern genetic engineering. The herpes simplex virus (HSV) family offers particular advantages for use as a viral oncolytic. The engineered vectors that make up oncolytic HSVs (oHSVs) have demonstrated remarkable safety in clinical trials, with some evidence of efficacy. The past decade has seen a focus on increasing the efficacy of oncolytic vectors by adding exogenous transgenes to enhance tumor destruction. The current paper describes the various strategies for engineering HSV for increased cancer tissue specificity and efficacy. Presented are the rationale, preclinical data and clinical data where available. This is meant to illustrate a basic framework for the development of a novel therapy meant to exploit the viral life cycle for the killing of cancer.
    Drugs of the Future 01/2010; 35(3):183-195. DOI:10.1358/dof.2010.35.3.1470166 · 0.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncolytic herpes simplex virus (oHSV)-1-based vectors selectively replicate in tumor cells causing direct killing, that is, oncolysis, while sparing normal cells. The oHSVs are promising anticancer agents, but their efficacy, when used as single agents, leaves room for improvement. We hypothesized that combining the direct oncolytic and antiangiogenic activities of the interleukin (IL)-12-secreting NV1042 oHSV with microtubule disrupting agents (MDAs) would be an effective means to enhance antitumor efficacy. Vinblastine (VB) was identified among several MDAs screened, which displayed consistent and potent cytotoxic killing of both prostate cancer and endothelial cell lines. In matrigel tube-forming assays, VB was found to be highly effective at inhibiting tube formation of human umbilical vein endothelial cells. The combination of VB with NV1023 (the parental virus lacking IL-12) or NV1042 showed additive or synergistic activity against prostate cancer cell lines, and was not due to increased oHSV replication by VB. In athymic mice bearing CWR22 prostate tumors, VB in combination with NV1042 was superior to the combination of VB plus NV1023 in reducing tumor burden, appeared to be nontoxic and resulted in a statistically significant diminution in the number of CD31(+) cells as compared with other treatment groups. In human organotypic cultures using surgical samples from radical prostatectomies, both NV1023 and NV1042 were localized specifically to the epithelial cells of prostatic glands but not to the surrounding stroma. These data highlight the therapeutic advantage of combining the dual-acting antitumor and antiangiogenic activities of oHSVs and MDAs.Cancer Gene Therapy advance online publication, 9 November 2012; doi:10.1038/cgt.2012.75.
    Cancer gene therapy 11/2012; DOI:10.1038/cgt.2012.75 · 3.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. Various types of HSV have been studied in basic or clinical research. Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. As an efficient gene delivery system, HSV has been successfully used to deliver various immunomodulatory molecules. Arming HSV with therapeutic genes merits further investigation for potential clinical application.
    Science China. Life sciences 04/2013; 56(4):298-305. DOI:10.1007/s11427-013-4466-4 · 1.51 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014