title: Natural killer cell therapy and aerosol interleukin-2 for the treatment of osteosarcoma lung metastasis.
abstract: BACKGROUND
  Survival of patients with osteosarcoma lung metastases has not improved in 20 years. We evaluated the efficacy of combining natural killer (NK) cells with aerosol interleukin-2 (IL-2) to achieve organ-specific NK cell migration and expansion in the metastatic organ, and to decrease toxicity associated with systemic IL-2.
  
  
  METHODS
  Five human osteosarcoma cell lines and 103 patient samples (47 primary and 56 metastatic) were analyzed for NKG2D ligand (NKG2DL) expression. Therapeutic efficacy of aerosol IL-2 + NK cells was evaluated in vivo compared with aerosol IL-2 alone and NK cells without aerosol IL-2.
  
  
  RESULTS
  Osteosarcoma cell lines and patient samples expressed various levels of NKG2DL. NK-mediated killing was NKG2DL-dependent and correlated with expression levels. Aerosol IL-2 increased NK cell numbers in the lung and within metastatic nodules but not in other organs. Therapeutic efficacy, as judged by tumor number, size, and quantification of apoptosis, was also increased compared with NK cells or aerosol IL-2 alone. There were no IL-2-associated systemic toxicities.
  
  
  CONCLUSIONS
  Aerosol IL-2 augmented the efficacy of NK cell therapy against osteosarcoma lung metastasis, without inducing systemic toxicity. Our data suggest that lung-targeted IL-2 delivery circumvents toxicities induced by systemic administration. Combining aerosol IL-2 with NK cell infusions, may be a potential new therapeutic approach for patients with osteosarcoma lung metastasis.
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sergei R
authors.initials: SR
authors.lastname: Guma
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.forename: Nancy
authors.initials: N
authors.lastname: Gordon
authors.forename: Dennis
authors.initials: D
authors.lastname: Hughes
authors.forename: John
authors.initials: J
authors.lastname: Stewart
authors.forename: Wei Lien
authors.initials: WL
authors.lastname: Wang
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D064987:Cell- and Tissue-Based Therapy; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423230:ULBP2 protein, human
keywords: aerosol interleukin-2; cytokines; immunotherapy; lung metastasis; natural killer cells; osteosarcoma