title: Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18.
abstract: BACKGROUND
  Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.
  
  
  METHODS
  Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack in vitro. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated in vivo in mice bearing ID8-Vegf tumors.
  
  
  RESULTS
  While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death in vitro. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy in vivo and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.
  
  
  CONCLUSIONS
  These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 in vivo.
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Alagkiozidis
authors.forename: Andrea
authors.initials: A
authors.lastname: Facciabene
authors.forename: Carmine
authors.initials: C
authors.lastname: Carpenito
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Jonak
authors.forename: Sarah
authors.initials: S
authors.lastname: Adams
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Rachel
authors.initials: R
authors.lastname: Hammond
authors.forename: Gwen-äel
authors.initials: GÄ
authors.lastname: Danet-Desnoyers
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004317:Doxorubicin / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D020382:Interleukin-18 / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D015996:Survival Rate
chemical_list: D000903:Antibiotics, Antineoplastic; D020382:Interleukin-18; D004317:Doxorubicin