title: Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells.
abstract: Carrier cells delivering a conditionally replicating adenovirus (CRAd), which selectively replicates in tumor cells and induces tumor cell lysis, have promising potential for treatment of cancer because CRAd-loaded carrier cells evade inhibition by neutralizing anti-adenovirus (Ad) antibodies and because the carrier cells are locally retained at the injection point after local injection. A previous study by Hamada et al. demonstrated that carrier cells (CRAd-containing cell fragments derived from the carrier cells) are engulfed into the target cells, probably through a pathway independent of the primary receptor for Ad, the coxsackievirus and Ad receptor (CAR) (Mol Ther, 15: 1121-1128; 2007); however, it remains to be elucidated whether carrier cells infected with a conventional CRAd, which is composed of subgroup-C Ad serotype-5 (Ad5), mediate antitumor effects on CAR-negative cells. In order to examine whether carrier cells delivering a conventional CRAd (Carrier-F5) induce lysis of CAR-negative tumor cells, CAR-positive and CAR-negative tumor cells were incubated with Carrier-F5. Carrier-F5 mediated efficient killing of CAR-positive tumor cells; however, CAR-negative tumor cells were almost refractory to Carrier-F5. On the other hand, carrier cells loaded with a fiber-substituted CRAd containing fiber proteins of Ad serotype-35 (Ad35) (CRAd-F35), which binds to human CD46 for infection, showed efficient killing of both CAR-positive and CAR-negative tumor cells. Intra-tumoral injection of carrier cells loaded with CRAd-F35 (Carrier-F35) also resulted in efficient regression of both CAR-positive and CAR-negative tumors. These results demonstrated that the expression levels of receptors for Ad are an important factor for CRAd-loaded carrier cell-mediated cancer therapy, and that Carrier-F35 would have potential as a cancer treatment for not only CAR-positive tumors but also CAR-negative tumors.
authors.affiliation: Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iguchi
authors.forename: F
authors.initials: F
authors.lastname: Sakurai
authors.forename: K
authors.initials: K
authors.lastname: Tomita
authors.forename: K
authors.initials: K
authors.lastname: Katayama
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: K
authors.initials: K
authors.lastname: Kawabata
authors.forename: M
authors.initials: M
authors.lastname: Tagawa
authors.forename: M
authors.initials: M
authors.lastname: Kawabata
authors.forename: T
authors.initials: T
authors.lastname: Shirakawa
authors.forename: H
authors.initials: H
authors.lastname: Mizuguchi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D000077192:Adenocarcinoma of Lung; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D051916:Membrane Cofactor Protein / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000379:methods*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000172:deficiency*; D014161:Transduction, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus