title: Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors.
abstract: Chimeric antigen receptor-modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HDPDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1exhibited no antitumor effect and CAd-VECPDL1alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1with HER2.CAR T cells enhanced antitumor activity compared with treatment with either HER2.CAR T cells alone or HER2.CAR T cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VECPDL1could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T cells and coadministration of Onc.Ad in an HER2+prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VECPDL1combined with administration of tumor-directed CAR T cells to control the growth of solid tumors.Cancer Res; 77(8); 2040-51. ©2017 AACR.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Tanoue
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
authors.forename: Amanda
authors.initials: A
authors.lastname: Rosewell Shaw
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
authors.forename: Caroline
authors.initials: C
authors.lastname: Porter
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
authors.forename: Bhakti
authors.initials: B
authors.lastname: Rana
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Brenner
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. suzuki@bcm.edu.|Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
authors.forename: Masataka
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000072283:A549 Cells; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins