title: Oncolytic Adenoviral Delivery of an EGFR-Targeting T-cell Engager Improves Antitumor Efficacy.
abstract: Antiviral immune responses present a major hurdle to the efficacious use of oncolytic adenoviruses as cancer treatments. Despite the existence of a highly immunosuppressive tumor environment, adenovirus-infected cells can nonetheless be efficiently cleared by infiltrating cytotoxic T lymphocytes (CTL) without compromising tumor burden. In this study, we tested the hypothesis that tumor-infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses that were armed with bispecific T-cell-engager (BiTE) antibodies. The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE, which retained its oncolytic propertiesin vitrocBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE-infected cells, and the secreted BiTEs bound specifically to both CD3+and EGFR+cells. In cell coculture assays, ICOVIR-15K-cBiTE-mediated oncolysis resulted in robust T-cell activation, proliferation, and bystander cell-mediated cytotoxicity. Notably, intratumoral injection of this cBiTE-expressing adenovirus increased the persistence and accumulation of tumor-infiltrating T cellsin vivo, compared with the parental virus lacking such effects. Moreover, in two distinct tumor xenograft models, combined delivery of ICOVIR-15K-cBiTE with peripheral blood mononuclear cells or T cells enhanced the antitumor efficacy achieved by the parental counterpart. Overall, our results show how arming oncolytic adenoviruses with BiTE can overcome key limitations in oncolytic virotherapy.Cancer Res; 77(8); 2052-63. ©2017 AACR.
authors.affiliation: ProCure Program, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Fajardo
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sonia
authors.initials: S
authors.lastname: Guedan
authors.affiliation: ProCure Program, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Luis Alfonso
authors.initials: LA
authors.lastname: Rojas
authors.affiliation: ProCure Program, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno
authors.affiliation: ProCure Program, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Marcel
authors.initials: M
authors.lastname: Arias-Badia
authors.affiliation: ProCure Program, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Jana
authors.initials: J
authors.lastname: de Sostoa
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: ProCure Program, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain. ralemany@iconcologia.net.
authors.forename: Ramon
authors.initials: R
authors.lastname: Alemany
mesh_terms: D000072283:A549 Cells; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D011897:Random Allocation; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; C512478:EGFR protein, human; D066246:ErbB Receptors