title: Evaluation of monocytes as carriers for armed oncolytic adenoviruses in murine and Syrian hamster models of cancer.
abstract: Replication-competent (oncolytic) adenoviruses (OAV) can be adapted as vectors for the delivery of therapeutic genes, with the aim of extending the antitumor effect beyond direct cytolysis. Transgene expression using these vectors is usually intense but short-lived, and repeated administrations are hampered by the rapid appearance of neutralizing antibodies (NAbs). We have studied the performance of monocytes as cell carriers to improve transgene expression in cancer models established in athymic mice and immunocompetent Syrian hamsters. Human and hamster monocytic cell lines (MonoMac6 and HM-1, respectively) were loaded with replication-competent adenovirus-expressing luciferase. Intravenous administration of these cells caused a modest increase in transgene expression in tumor xenografts, but this effect was virtually lost in hamsters. In contrast, intratumoral administration of HM-1 cells allowed repeated cycles of expression and achieved partial protection from NAbs in preimmunized hamsters bearing pancreatic tumors. To explore the therapeutic potential of this approach, HM-1 cells were loaded with a hypoxia-inducible OAV expressing the immunostimulatory cytokine interleukin-12 (IL-12). Three cycles of treatment achieved a significant antitumor effect in the hamster model, and transgene expression was detected following each administration, in contrast with the rapid neutralization of the free virus. We propose monocytes as carriers for multiple intratumoral administrations of armed OAVs.
authors.affiliation: Division of Hepatology and Gene Therapy, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Bunuales
authors.forename: Eva
authors.initials: E
authors.lastname: Garcia-Aragoncillo
authors.forename: Raquel
authors.initials: R
authors.lastname: Casado
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Quetglas
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.forename: Sergia
authors.initials: S
authors.lastname: Bortolanza
authors.forename: Carolina
authors.initials: C
authors.lastname: Benavides-Vallve
authors.forename: Carlos
authors.initials: C
authors.lastname: Ortiz-de-Solorzano
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernandez-Alcoceba
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000472:pathogenicity; D000818:Animals; D006224:Cricetinae; D015870:Gene Expression; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000821:virology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy; D019076:Transgenes; D019737:Transplants / Q000821:virology; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D018664:Interleukin-12