title: Viral infection of implanted meningeal tumors induces antitumor memory T-cells to travel to the brain and eliminate established tumors.
abstract: BACKGROUND
  Leptomeningeal metastases occur in 2%-5% of patients with breast cancer and have an exceptionally poor prognosis. The blood-brain and blood-meningeal barriers severely inhibit successful chemotherapy. We have developed a straightforward method to induce antitumor memory T-cells using a Her2/neu targeted vesicular stomatitis virus. We sought to determine whether viral infection of meningeal tumor could attract antitumor memory T-cells to eradicate the tumors.
  
  
  METHODS
  Meningeal implants in mice were studied using treatment trials and analyses of immune cells in the tumors.
  
  
  RESULTS
  This paper demonstrates that there is a blood-meningeal barrier to bringing therapeutic memory T-cells to meningeal tumors. The barrier can be overcome by viral infection of the tumor. Viral infection of the meningeal tumors followed by memory T-cell transfer resulted in 89% cure of meningeal tumor in 2 different mouse strains. Viral infection produced increased infiltration and proliferation of transferred memory T-cells in the meningeal tumors. Following viral infection, the leukocyte infiltration in meninges and tumor shifted from predominantly macrophages to predominantly T-cells. Finally, this paper shows that successful viral therapy of peritoneal tumors generates memory CD8 T-cells that prevent establishment of tumor in the meninges of these same animals.
  
  
  CONCLUSIONS
  These results support the hypothesis that a virally based immunization strategy can be used to both prevent and treat meningeal metastases. The meningeal barriers to cancer therapy may be much more permeable to treatment based on cells than treatment based on drugs or molecules.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Y.G.); Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.W.-D.); Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, American University Hospital, Beirut, Lebanon (M.A.B.); Department of Immunology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania (P.H.B.); Department of Pediatrics, Department of Neurology, and Department of Immunology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania (I.B.).
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Y.G.); Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.W.-D.); Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, American University Hospital, Beirut, Lebanon (M.A.B.); Department of Immunology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania (P.H.B.); Department of Pediatrics, Department of Neurology, and Department of Immunology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania (I.B.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Whitaker-Dowling
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Y.G.); Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.W.-D.); Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, American University Hospital, Beirut, Lebanon (M.A.B.); Department of Immunology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania (P.H.B.); Department of Pediatrics, Department of Neurology, and Department of Immunology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania (I.B.).
authors.forename: Mamdouha A
authors.initials: MA
authors.lastname: Barmada
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Y.G.); Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.W.-D.); Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, American University Hospital, Beirut, Lebanon (M.A.B.); Department of Immunology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania (P.H.B.); Department of Pediatrics, Department of Neurology, and Department of Immunology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania (I.B.).
authors.forename: Per H
authors.initials: PH
authors.lastname: Basse
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Y.G.); Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.W.-D.); Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, American University Hospital, Beirut, Lebanon (M.A.B.); Department of Immunology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania (P.H.B.); Department of Pediatrics, Department of Neurology, and Department of Immunology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania (I.B.).
authors.forename: Ira
authors.initials: I
authors.lastname: Bergman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive; D053208:Kaplan-Meier Estimate; D008577:Meningeal Neoplasms / Q000556:secondary / Q000628:therapy* / Q000821:virology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D016896:Treatment Outcome; D018116:Vesiculovirus
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: VSV; blood-meningeal barrier; memory T-cells; meningeal tumor; viral therapy