title: Mesenchymal Stromal Cells for Linked Delivery of Oncolytic and Apoptotic Adenoviruses to Non-small-cell Lung Cancers.
abstract: Oncolytic adenoviruses (OAdV) represent a promising strategy for cancer therapy. Despite their activity in preclinical models, to date the clinical efficacy remains confined to minor responses after intratumor injection. To overcome these limitations, we developed an alternative approach using the combination of the OAdv ICOVIR15 with a replication incompetent adenoviral vector carrying the suicide gene of inducible Caspase 9 (Ad.iC9), both of which are delivered by mesenchymal stromal cells (MSCs). We hypothesized that coinfection with ICOVIR15 and Ad.iC9 would allow MSCs to replicate both vectors and deliver two distinct types of antitumor therapy to the tumor, amplifying the cytotoxic effects of the two viruses, in a non-small-cell lung cancer (NSCLC) model. We showed that MSCs can replicate and release both vectors, enabling significant transduction of the iC9 gene in tumor cells. In the in vivo model using human NSCLC xenografts, MSCs homed to lung tumors where they released both viruses. The activation of iC9 by the chemical inducer of dimerization (CID) significantly enhanced the antitumor activity of the ICOVIR15, increasing the tumor control and translating into improved overall survival of tumor-bearing mice. These data support the use of this innovative approach for the treatment of NSCLC.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Hoyos
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.|Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Del Bufalo
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yagyu
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Miki
authors.initials: M
authors.lastname: Ando
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Masataka
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.|Department of Pediatrics-Hematology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bouchier-Hayes
authors.affiliation: Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Alemany
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D015552:Injections, Intralesional; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000235:genetics; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics; D014161:Transduction, Genetic; D019076:Transgenes; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D011993:Recombinant Fusion Proteins; D053453:Caspase 9; D022061:Tacrolimus Binding Protein 1A