title: T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy.
abstract: Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. However, complete responses have rarely been observed. This lack of efficacy is most likely due to suboptimal virus spread through the tumor resulting in limited tumor cell destruction. We reasoned that redirecting T cells to the tumor has the potential to improve the antitumor activity of oncolytic VVs. We, therefore, constructed a VV encoding a secretory bispecific T-cell engager consisting of two single- chain variable fragments specific for CD3 and the tumor cell surface antigen EphA2 (EphA2-T-cell engager-armed VV (EphA2-TEA-VV)). In vitro, EphA2-TEA-VV's ability to replicate and induce oncolysis was similar to that of unmodified virus. However, only tumor cells infected with EphA2-TEA-VV induced T-cell activation as judged by the secretion of interferon-γ and interleukin-2. In coculture assays, EphA2-TEA-VV not only killed infected tumor cells, but in the presence of T cells, it also induced bystander killing of noninfected tumor cells. In vivo, EphA2-TEA-VV plus T cells had potent antitumor activity in comparison with control VV plus T cells in a lung cancer xenograft model. Thus, arming oncolytic VVs with T-cell engagers may represent a promising approach to improve oncolytic virus therapy.
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xingbing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Z Sheng
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: 1] Center for Cell and Gene Therapy, Texas Children's Hospital, The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA [3] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA [4] Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Gottschalk
authors.affiliation: 1] Center for Cell and Gene Therapy, Texas Children's Hospital, The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Song
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology*; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D017252:CD3 Complex; D036104:Receptor, EphA2