title: Retargeting Strategies for Oncolytic Herpes Simplex Viruses.
abstract: 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.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. gabriella.campadelli@unibo.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Campadelli-Fiume
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. bily.p@hotmail.it.
authors.forename: Biljana
authors.initials: B
authors.lastname: Petrovic
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. valerio.leoni2@unibo.it.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. tatiana.gianni3@unibo.it.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gianni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. elisa.avitabile@unibo.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Avitabile
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. costanza.casiraghi@unibo.it.
authors.forename: Costanza
authors.initials: C
authors.lastname: Casiraghi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. valentina.gatta6@unibo.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gatta
mesh_terms: D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*; D056189:Viral Tropism; D053586:Virus Internalization
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011991:Receptors, Virus; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D015678:Viral Structural Proteins; C508053:ERBB2 protein, human
keywords: HER-2; oncolytic HSV; retargeting