2026-04-17T05:13:50Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1716902025-12-05T12:38:56Zcom_2072_1057col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Sostoa, Jana de author Fajardo Calderón, Carlos Alberto author Moreno Olié, Rafael author Ramos, Maria D. author Farrera Sal, Martí author Alemany Bonastre, Ramon author 2020-11-02T10:18:22Z 2020-11-02T10:18:22Z 2019-01-25 2020-10-26T09:26:53Z 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. Tumors Adenovirus Oncologia Adenoviruses Oncology Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager