Herpes simplex virus 1 (HSV-1) for cancer treatment

Shen, Yuqiao; Nemunaitis, John

doi:10.1038/sj.cgt.7700946

Cited by 133 publications

(106 citation statements)

References 215 publications

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“…Theoretical considerations and experimental observations made thus far indicate that mechanisms of tumor resistance to HSV-1 therapy include ECM-mediated impairment of intratumoral virus spread, impaired viral entry into tumor cells because of decreased expression of HSV-1 entry receptors, inhibition of viral replication after viral entry into tumor cells, and virus clearance by the host immune system. [5][6][7][12][13][14][15][17][18] In this study, we found that at least two of these potential mechanisms of virus resistanceimpaired virus spread in the ECM and inhibition of viral replication after viral entry into tumor cells-are also relevant to 3D tumor cell cultures.…”

Section: Discussionmentioning

confidence: 88%

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Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

et al. 2009

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To better understand melanoma resistance to herpes simplex virus type 1 (HSV-1)-mediated oncolysis, traditional two-dimensional (2D) cultures and extracellular matrix (ECM) containing three-dimensional (3D) cultures of OCM1 and C918 uveal melanoma cells were infected with an HSV-1 strain that expresses the green fluorescent protein (GFP) marker during replication. Although 2D cultures were completely destroyed within a few days of HSV-1 inoculation, viable GFP-negative tumor cells remained detectable in 3D cultures for several weeks. Tumor cells with increased resistance to HSV-1 included cells that formed vasculogenic mimicry patterns and multicellular spheroids and cells that invaded Matrigel individually. Mechanisms of tumor resistance against HSV-1 in the 3D environment included impaired virus spread in the ECM and ECM-mediated inhibition of viral replication after viral entry into tumor cells. Observations also suggested that HSV-1 established quiescent infection in some tumor cells present in multicellular spheroids and that this could revert to productive viral infection when the tumor growth pattern changed. These findings indicate that 3D tumor cell cultures can be used to identify distinct tumor cell populations with increased resistance to HSV-1 and to explore mechanisms of ECM-mediated tumor resistance to oncolytic virotherapy.

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Section: Discussionmentioning

confidence: 88%

“…[1][2][3][4][5][6] Oncolytic HSV-1 therapy is dependent on virus replication in tumor cells and is augmented by host antiviral and infection-induced anti-tumor immune responses. [7][8][9][10][11] In spite of significant progress, oncolytic virotherapy faces significant challenges.…”

Section: Introductionmentioning

confidence: 99%

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

et al. 2009

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“…The most commonly used TK for gene therapy studies is HSV-TK in combination with an acycloguanosine such as ganciclovir which has been tested in a series of pre-clinical and clinical trials in a wide range of cancer types. 111,112 The potential exists to improve this study by combining it with multi-modality imaging techniques such as SPECT, PET or MRI. Combined application of the imaging modalities and imaging probes will maximize the diagnostic and therapeutic potential of bacterial gene therapy and achieve a targeted regime for cancer therapy with minimal off-target effects.…”

Section: Combined Imaging and Therapymentioning

confidence: 99%

Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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The significant burden of resistance to conventional anticancer treatments in patients with advanced disease has prompted the need to explore alternative therapeutic strategies. The challenge for oncology researchers is to identify a therapy which is selective for tumors with limited toxicity to normal tissue. Engineered bacteria have the unique potential to overcome traditional therapies' limitations by specifically targeting tumors. It has been shown that bacteria are naturally capable of homing to tumors when systemically administered resulting in high levels of replication locally, either external to (non-invasive species) or within tumor cells (pathogens). Pre-clinical and clinical investigations involving bacterial vectors require relevant means of monitoring vector trafficking and levels over time, and development of bacterial-specific real-time imaging modalities are key for successful development of clinical bacterial gene delivery. This review discusses the currently available imaging technologies and the progress to date exploiting these for monitoring of bacterial gene delivery in vivo.Cancer Gene Therapy ( INTRODUCTIONAlthough the potential anti-cancer effects of acquired bacterial infection have been evident for over 120 years and the presence of bacteria in excised tumors has been noted for over 60 years, 1 it is only in more recent times that the tumor-specific growth of bacteria has been considered for therapeutic purposes. While the precise mechanism(s) behind preferential bacterial tumor colonization remain poorly understood, this phenomenon must relate to unique tumor attributes that separate them from healthy tissues. Factors such as the irregular blood supply; local immune suppression; inflammation; and unique nutrient supply (e.g., purines) in tumors have been proposed to play a role. 2 Bacterial entry into the tumor environment is proposed to be facilitated by the leaky vasculature. Cancer cells are characterized by an aberrantly accelerated metabolism and proliferation leading to an imbalance of oxygen supply and consumption which is a major causative factor of tumor hypoxia. 3 The hypoxic nature of solid tumors enhances the growth of anaerobic and facultatively anaerobic bacteria. In addition, these areas with low oxygen and high interstitial pressure are considered to be an immunological sanctuary, where bacterial clearance mechanisms are greatly inhibited. 4 Necrotic regions are also rich in nutrients favoured by bacteria due to tumor cell turnover. However, tumor selective bacterial colonization now appears to be both bacterial species and tumor origin independent, since aerobic bacteria are also capable of colonising tumors, and even small tumors lacking an anaerobic center are colonised. See Figure 1 for proposed mechanisms.Invasive bacteria can internalize and replicate within tumor cells, while non-invasive bacteria grow externally to tumor cells, within the tumor micro-environment. 5 The tumor selective growth of bacteria has made them an attractive vehicle for the delivery of ...

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“…This strategy, also called prodrugactivating gene therapy, offers the potential for selective tumor destruction without inducing significant systemic toxicity. 9,10 The thymidine kinase (TK) from herpes simplex virus (HSV) is the best characterized suicide gene. 11 Expression of functional HSV-TK in transduced cells has the ability to transform a nontoxic prodrug such as ganciclovir (GCV) into a toxic phosphorylated (GCVtriphosphate) compound that competes with triphosphate as a substrate for DNA polymerase.…”

Section: Introductionmentioning

confidence: 99%

A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

et al. 2010

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The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10 10 to 2 Â 10 12 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 Â 10 12 vp per patient.

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Herpes simplex virus 1 (HSV-1) for cancer treatment

Cited by 133 publications

References 215 publications

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

Bacterial vectors for imaging and cancer gene therapy: a review

A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

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