The Engineering of a Novel Ligand in gH Confers to HSV an Expanded Tropism Independent of gD Activation by Its Receptors

Gatta, Valentina; Petrovic, Biljana; Campadelli-Fiume, Gabriella

doi:10.1371/journal.ppat.1004907

Cited by 28 publications

(44 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This property is consistent with the detargeting effect of the partial deletion in gD. In conclusion, we have defined the site of insertion of scFv to HER2 in gH and ascertained that it can be coupled with gD deletions for detargeting from natural receptors [ 64 ]. These findings support two key conclusions: (i) it is possible to modify HSV tropism through the insertion of a heterologous ligand in gH; and (ii) a gH-retargeted-HSV is infectious even in the absence of a gD receptor capable of activating gD.…”

Section: Tropism Retargeting Based On Modifications Of Ghsupporting

confidence: 67%

See 1 more Smart Citation

Retargeting Strategies for Oncolytic Herpes Simplex Viruses

Campadelli-Fiume

Petrovic

Leoni

et al. 2016

Viruses

Self Cite

View full text Add to dashboard Cite

Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER-2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors’ binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER-2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules.

show abstract

Section: Tropism Retargeting Based On Modifications Of Ghsupporting

confidence: 67%

“…R-VG803 carries a wt-gD. R-VG809 carries the deletion of AA 6–38 region in gD for detargeting purposes [ 64 ]. The redirected tropism of R-VG803 and R-VG809 to HER2 was documented as the ability to infect the receptor-negative J cells transgenically expressing a single receptor, i.e.…”

Section: Tropism Retargeting Based On Modifications Of Ghmentioning

confidence: 99%

Retargeting Strategies for Oncolytic Herpes Simplex Viruses

Campadelli-Fiume

Petrovic

Leoni

et al. 2016

Viruses

Self Cite

View full text Add to dashboard Cite

show abstract

“…R-VG809 was the first receptor retargeted mutant to show replication equal to the parental virus, at least in HER-2 positive ovarian cancer cells. 76 …”

Section: Generation Of Ohsvsmentioning

confidence: 99%

Oncolytic virotherapy using herpes simplex virus: how far have we come?

Sokolowski

Rizos²,

Diefenbach

2015

View full text Add to dashboard Cite

Oncolytic virotherapy exploits the properties of human viruses to naturally cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV) has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future.

show abstract

“…An alternative strategy to attenuation is tropism retargeting, whereby the viral tropism is retargeted to cancer-specific receptors of choice and detargeted from natural receptors; the viruses are otherwise wt, i.e., nonattenuated ( 18 – 22 ). In our laboratory, we selected as the target receptor human epidermal growth factor receptor 2 (HER2) ( 20 , 22 – 27 ), a member of the epidermal growth factor receptor (EGFR) family of receptors, present in a subset of breast, ovary, stomach, and lung cancers. The patients carrying HER2-positive tumors are treated with the anti-HER2 humanized antibodies trastuzumab and/or pertuzumab ( 28 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

Dual Ligand Insertion in gB and gD of Oncolytic Herpes Simplex Viruses for Retargeting to a Producer Vero Cell Line and to Cancer Cells

Petrovic

Leoni

Gatta

et al. 2018

J Virol

Self Cite

View full text Add to dashboard Cite

Oncolytic viruses gain cancer specificity in several ways. Like the majority of viruses, they grow better in cancer cells that are defective in mounting the host response to viruses. Often, they are attenuated by deletion or mutation of virulence genes that counteract the host response or are naturally occurring oncolytic mutants. In contrast, retargeted viruses are not attenuated or deleted; their cancer specificity rests on a modified, specific tropism for cancer receptors. For herpes simplex virus (HSV)-based oncolytics, the detargeting-retargeting strategies employed so far were based on genetic modifications of gD. Recently, we showed that even gH or gB can serve as retargeting tools. To enable the growth of retargeted HSVs in cells that can be used for clinical-grade virus production, a double-retargeting strategy has been developed. Here we show that several sites in the N terminus of gB are suitable to harbor the 20-amino-acid (aa)-long GCN4 peptide, which readdresses HSV tropism to Vero cells expressing the artificial GCN4 receptor and thus enables virus cultivation in the producer noncancer Vero-GCN4R cell line. The gB modifications can be combined with a minimal detargeting modification in gD, consisting in the deletion of two residues, aa 30 and 38, and replacement of aa 38 with the scFv to human epidermal growth factor receptor 2 (HER2), for retargeting to the cancer receptor. The panel of recombinants was analyzed comparatively in terms of virus growth, cell-to-cell spread, cytotoxicity, and in vivo antitumor efficacy to define the best double-retargeting strategy.IMPORTANCE There is increasing interest in oncolytic viruses, following FDA and the European Medicines Agency (EMA) approval of HSV OncovexGM-CSF, and, mainly, because they greatly boost the immune response to the tumor and can be combined with immunotherapeutic agents, particularly checkpoint inhibitors. A strategy to gain cancer specificity and avoid virus attenuation is to retarget the virus tropism to cancer-specific receptors of choice. Cultivation of fully retargeted viruses is challenging, since they require cells that express the cancer receptor. We devised a strategy for their cultivation in producer noncancer Vero cell derivatives. Here, we developed a double-retargeting strategy, based on insertion of one ligand in gB for retargeting to a Vero cell derivative and of anti-HER2 ligand in gD for cancer retargeting. These modifications were combined with a minimally destructive detargeting strategy. This study and its companion paper explain the clinical-grade cultivation of retargeted oncolytic HSVs and promote their translation to the clinic.

show abstract

The Engineering of a Novel Ligand in gH Confers to HSV an Expanded Tropism Independent of gD Activation by Its Receptors

Cited by 28 publications

References 60 publications

Retargeting Strategies for Oncolytic Herpes Simplex Viruses

Retargeting Strategies for Oncolytic Herpes Simplex Viruses

Oncolytic virotherapy using herpes simplex virus: how far have we come?

Dual Ligand Insertion in gB and gD of Oncolytic Herpes Simplex Viruses for Retargeting to a Producer Vero Cell Line and to Cancer Cells

Contact Info

Product

Resources

About