title: EGFR-homing dsRNA activates cancer-targeted immune response and eliminates disseminated EGFR-overexpressing tumors in mice.
abstract: OBJECTIVE
  The cause of most cancer deaths is incurable dissemination of cancer cells into vital organs. Current systemic therapies for disseminated cancers provide limited efficacy and are often accompanied by toxic side effects. We have recently shown that local application of epidermal growth factor receptor (EGFR)-targeted polyinosine-cytosine (polyIC) eradicates preestablished EGFR-overexpressing tumors. Here we show for the first time the high efficiency of systemic application of polyIC/melittin-polyethyleneimine-polyethyleneglycol-EGF (polyIC/MPPE) in combination with human immune cells.
  
  
  METHODS
  Cancer-targeted activation of immune cells was examined in vitro and in vivo following transfection with polyIC/MPPE. The therapeutic efficiency of the strategy was then examined on disseminated EGFR-overexpressing tumors grown in severe combined immunodeficient (SCID) mice.
  
  
  RESULTS
  Intravenous delivery of polyIC/MPPE followed by intraperitoneal injection of peripheral blood mononuclear cells induced the complete cure of SCID mice with preestablished disseminated EGFR-overexpressing tumors, with no adverse toxic effects. The immune cells and the cytokines they produce are localized to the tumor site of the treated animal and contribute decisively to the demise of the tumor cells. The immune system homes to the tumors, due to the chemokines produced by the internalized polyIC.
  
  
  CONCLUSIONS
  The EGFR-homing vector loaded with polyIC can be used to treat and possibly cure patients with disseminated EGFR-overexpressing tumors. The possibility of adopting this strategy to treat other tumors that express a protein capable of ligand induced internalization is discussed.
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
authors.forename: Alexei
authors.initials: A
authors.lastname: Shir
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Roedl
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008555:Melitten / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011070:Poly I-C / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011094:Polyethyleneimine / Q000627:therapeutic use; D012330:RNA, Double-Stranded / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D012330:RNA, Double-Stranded; D008555:Melitten; D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor; D011094:Polyethyleneimine; D066246:ErbB Receptors; D011070:Poly I-C