title: Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice.
abstract: BACKGROUND
  Combination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. In particular, a combination of three agonist antibodies, termed Tri-mAb, consisting of anti-DR5, anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma (Renca) tumors (75% long-term survival), but the effect against orthotopic disease is not known.
  
  
  OBJECTIVE
  To determine the relative response of orthotopic tumors, we inoculated Renca into the kidney followed by treatment with Tri-mAb.
  
  
  RESULTS
  We found that orthotopic tumors responded much less to treatment (approximately 13% survival), but a significant improvement in survival was achieved through the addition of IL-2 to the treatment regimen (55% survival). All three agonist antibodies and high dose IL-2, 100,000 IU for up to six doses, were required. CD8+ T cells were also required for optimal anti-tumor responses. Coadministration of IL-2 led to enhanced T cell activity as demonstrated by an increased frequency of IFN-gamma-producing T cells in tumor-draining lymph nodes, which may have contributed to the observed improvement of therapy against kidney tumors.
  
  
  CONCLUSIONS
  Responses of subcutaneous tumors to immunotherapy do not necessarily reflect how orthotopic tumors respond. The use of combination immunotherapy stimulating multiple facets of immunity and including cytokine support for T cells can induce effective anti-tumor responses against orthotopic and metastatic tumors.
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.forename: Preethi Mayura
authors.initials: PM
authors.lastname: Guru
authors.forename: Janelle
authors.initials: J
authors.lastname: Sharkey
authors.forename: Hollie J
authors.initials: HJ
authors.lastname: Pegram
authors.forename: Sally M
authors.initials: SM
authors.lastname: Amos
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007376:Interleukin-2; D007371:Interferon-gamma