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http://hdl.handle.net/2445/171690
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DC Field | Value | Language |
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dc.contributor.author | Sostoa, Jana de | - |
dc.contributor.author | Fajardo Calderón, Carlos Alberto | - |
dc.contributor.author | Moreno Olié, Rafael | - |
dc.contributor.author | Ramos, Maria D. | - |
dc.contributor.author | Farrera Sal, Martí | - |
dc.contributor.author | Alemany Bonastre, Ramon | - |
dc.date.accessioned | 2020-11-02T10:18:22Z | - |
dc.date.available | 2020-11-02T10:18:22Z | - |
dc.date.issued | 2019-01-25 | - |
dc.identifier.uri | http://hdl.handle.net/2445/171690 | - |
dc.description.abstract | BackgroundOncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor-associated stroma limits the efficacy of oncolytic viruses by forming a barrier that blocks efficient viral penetration and spread. The stroma also plays a critical role in progression, immunosuppression and invasiveness of cancer. Fibroblast activation protein- (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs), the main cellular component of tumor stroma, and in this study we assessed whether arming oncolytic adenovirus (OAd) with a FAP-targeting Bispecific T-cell Engager (FBiTE) could retarget infiltrated lymphocytes towards CAFs, enhancing viral spread and T cell-mediated cytotoxicity against the tumor stroma to improve therapeutic activity.MethodsThe bispecific T-cell Engager against FAP was constructed using an anti-human CD3 single-chain variable fragment (scFv) linked to an anti-murine and human FAP scFv. This FBiTE was inserted in the oncolytic adenovirus ICOVIR15K under the control of the major late promoter, generating the ICO15K-FBiTE. ICO15K-FBiTE replication and potency were assessed in HT1080 and A549 tumor cell lines. The expression of the FBiTE and the activation and proliferation of T cells that induced along with the T cell-mediated cytotoxicity of CAFs were evaluated by flow cytometry in vitro.In vivo, T-cell biodistribution and antitumor efficacy studies were conducted in NOD/scid/IL2rg(-)/(-) (NSG) mice.ResultsFBiTE expression did not decrease the infectivity and replication potency of the armed virus. FBiTE-mediated binding of CD3(+) effector T cells and FAP(+) target cells led to T-cell activation, proliferation, and cytotoxicity of FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. The antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus.ConclusionsCombination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP-expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development. | - |
dc.format.extent | 15 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Bmc | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1186/s40425-019-0505-4 | - |
dc.relation.ispartof | Journal For Immunotherapy Of Cancer, 2019-01-25, Vol. 7, num. 19 | - |
dc.relation.uri | https://doi.org/10.1186/s40425-019-0505-4 | - |
dc.rights | cc by (c) Sostoa, Jana de et al., 2019 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Tumors | - |
dc.subject.classification | Adenovirus | - |
dc.subject.classification | Oncologia | - |
dc.subject.other | Adenoviruses | - |
dc.subject.other | Oncology | - |
dc.title | Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2020-10-26T09:26:53Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 30683154 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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File | Description | Size | Format | |
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de SostoaJ.pdf | 4.41 MB | Adobe PDF | View/Open |
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