title: Use of reverse genetics to enhance the oncolytic properties of Newcastle disease virus.
abstract: Naturally occurring strains of Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. Here, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of reverse genetics. Mice bearing s.c. implanted CT26 tumors were treated with intratumoral (i.t.) injections of a recombinant NDV modified to contain a highly fusogenic F protein. These treated mice exhibited significant reduction in tumor development compared with mice treated with the unmodified virus. Furthermore, mice in a CT26 metastatic tumor model treated with an i.v. injection of the genetically engineered NDV exhibited prolonged survival compared with wild-type control virus. In addition, we examined whether the oncolytic properties of NDV could be improved by expression of immunostimulatory molecules. In this regard, we engineered several NDVs to express granulocyte macrophage colony-stimulating factor, IFN-gamma, interleukin 2 (IL-2), or tumor necrosis factor alpha, and evaluated their therapeutic potential in an immunocompetent colon carcinoma tumor model. Mice bearing s.c. CT26 tumors treated with i.t. injections of recombinant NDV expressing IL-2 showed dramatic reductions in tumor growth, with a majority of the mice undergoing complete and long-lasting remission. Our data show the use of reverse genetics to develop enhanced recombinant NDV vectors as effective therapeutic agents for cancer treatment.
authors.affiliation: Department of Microbiology, Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Vigil
authors.forename: Man-Seong
authors.initials: MS
authors.lastname: Park
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Martinez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Chua
authors.forename: Sa
authors.initials: S
authors.lastname: Xiao
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Cros
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Sobrido
authors.forename: Savio L C
authors.initials: SL
authors.lastname: Woo
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000628:therapy*; D003110:Colonic Neoplasms / Q000628:therapy*; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009522:Newcastle disease virus / Q000235:genetics*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D047368:Tumor Burden; D014407:Tumor Cells, Cultured