title: Therapeutic efficacy of the F8-IL2 immunocytokine in a metastatic mouse model of lung adenocarcinoma.
abstract: OBJECTIVE
  Antibody-cytokine fusion proteins (immunocytokines) represent a novel class of armed antibodies in oncology. In particular, IL2- and TNF-based immunocytokines targeting the EDB domain of fibronectin and the A1 domain of tenascin-C have demonstrated promising anti-tumor activity and are currently investigated in Phase I and Phase II clinical trials. To advance the development of immunocytokines for NSCLC, we here report on the therapeutic efficacy of F8-IL2, an immunocytokine directed against the alternatively spliced EDA domain of fibronectin in a fully immunocompetent, orthotopic model of NSCLC, and the characterization of the target antigen expression in human NSCLC specimens.
  
  
  METHODS
  We evaluated the therapeutic efficacy of the F8-IL2 immunocytokine utilizing a K-ras mutant, p53 deficient metastatic mouse model of NSCLC derived from the latest generation of genetically engineered and conditional tumor models. In parallel, we assessed the presence of the EDA domain of fibronectin by immunofluorescence in lung biopsies obtained from patients with NSCLC.
  
  
  RESULTS
  The EDA domain of fibronectin was broadly expressed in lung metastases obtained from our model. Treatment with F8-IL2 induced substantial local changes within immune effector cell populations and demonstrated promising therapeutic efficacy as monotherapy. The target of F8-IL2, the EDA domain of fibronectin, was present in all human lung adenocarcinoma specimens tested.
  
  
  CONCLUSIONS
  Both the therapeutic efficacy in a metastatic mouse model of NSCLC and the extensive presence of the EDA domain of fibronectin in human NSCLC biopsies support the rational development of therapies based on the F8-IL2 immunocytokine for the treatment of NSCLC.
authors: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors: Sébastien
authors: S
authors: Wieckowski
authors: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland; Philochem AG, Libernstrasse 3, CH-8093 Otelfingen, Switzerland.
authors: Teresa
authors: T
authors: Hemmerle
authors: Institute of Pathology, University Hospital Basel, Schönebeinstrasse 40, CH-4003 Basel, Switzerland.
authors: Spasenja Savic
authors: SS
authors: Prince
authors: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors: Béatrice Dolder
authors: BD
authors: Schlienger
authors: Department of Thoracic Surgery, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
authors: Sven
authors: S
authors: Hillinger
authors: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland; Philochem AG, Libernstrasse 3, CH-8093 Otelfingen, Switzerland.
authors: Dario
authors: D
authors: Neri
authors: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Medical Oncology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: Alfred.Zippelius@usb.ch.
authors: Alfred
authors: A
authors: Zippelius
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C000603141:F8-IL2 immunocytokine; D011993:Recombinant Fusion Proteins
keywords: CD8 T-cells; Human; Immunocytokine; Immunofluorescence; Lung cancer; Mouse