title: Treatment of experimental murine pancreatic peritoneal carcinomatosis with fibroblasts genetically modified to express IL12: a role for peritoneal innate immunity.
abstract: BACKGROUND
  Peritoneal carcinomatosis from pancreatic cancer has a poor prognosis with a median survival of 3.1 months. This is mainly due to lack of effective treatment. Interleukin 12 (IL12) is a proinflammatory cytokine that has a potent antitumoral effect by stimulating innate and adoptive immunity.
  
  
  OBJECTIVE
  To examine the antitumoral effect and toxicity of intraperitoneal delivery of IL12 using an ex vivo gene therapy approach in a murine model of pancreatic peritoneal carcinomatosis.
  
  
  METHODS
  Peritoneal carcinomatosis was generated by direct intraperitoneal inoculation of the pancreatic cancer cell line Capan-1 in athymic mice. Syngenic fibroblasts were genetically modified in vitro to secrete IL12 using a polycistronic TFG murine IL12 retroviral vector coding for both p35 and p40 murine IL12 subunits. Ex vivo gene therapy involved injection of the genetically modified fibroblasts intraperitoneally twice a week for 4 weeks.
  
  
  RESULTS
  Treatment of pre-established peritoneal carcinomatosis with fibroblasts genetically modified to express IL12 induced a marked inhibition of tumour growth as measured by comparison of the weights of the intraperitoneal tumour nodules in the treated and control animals (3.52 (SD 0.47) v 0.93 (SD 0.21) g, p<0.05) and improved survival. This effect was associated with infiltration of the peritoneal tumour nodules with macrophages. Peritoneal lavage confirmed enhancement of the innate peritoneal inflammatory activity, with an increased number of activated macrophages and natural killer cells. Moreover, macrophages harvested from animals with peritoneal carcinomatosis and treated with IL12-expressing fibroblasts expressed an activated proinflammatory antitumoral M1 phenotype that included strongly enhanced reactive oxygen species and nitric oxide production. There was no treatment-related toxicity.
  
  
  CONCLUSIONS
  Multiple injections of genetically modified fibroblasts to express IL12 is an effective and well-tolerated treatment for experimental murine pancreatic peritoneal carcinomatosis via activated innate immunity and in particular activated M1 macrophages.
authors.affiliation: INSERM U531, Toulouse, France. peron.jm@chu-toulouse.fr
authors.forename: J M
authors.initials: JM
authors.lastname: Péron
authors.forename: C
authors.initials: C
authors.lastname: Bureau
authors.forename: P
authors.initials: P
authors.lastname: Gourdy
authors.forename: H
authors.initials: H
authors.lastname: Lulka
authors.forename: A
authors.initials: A
authors.lastname: Souque
authors.forename: B
authors.initials: B
authors.lastname: Calippe
authors.forename: J
authors.initials: J
authors.lastname: Selves
authors.forename: T
authors.initials: T
authors.lastname: Al Saati
authors.forename: J
authors.initials: J
authors.lastname: Bernad
authors.forename: P
authors.initials: P
authors.lastname: Cordelier
authors.forename: B
authors.initials: B
authors.lastname: Couderc
authors.forename: L
authors.initials: L
authors.lastname: Pradayrol
authors.forename: B
authors.initials: B
authors.lastname: Pipy
authors.forename: L
authors.initials: L
authors.lastname: Buscail
authors.forename: J P
authors.initials: JP
authors.lastname: Vinel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D005434:Flow Cytometry / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry / Q000379:methods; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009569:Nitric Oxide / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D018664:Interleukin-12; D009569:Nitric Oxide